Tri- and bi-cyclic heteroaryl histamine-3 receptor ligands

ABSTRACT

Compounds of formula (I) 
                         
wherein R 1  or R 2  is a tricyclic or bicyclic ring, each of which contains at least two heteroatoms, and R 1 , R 2 , R 3 , R 3a , R 3b , R 4 , R 5 , L, X, X′, Y, Y′, Z, and Z′ are as defined herein, are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands, methods for using such compounds and compositions, and a process for preparing compounds within the scope of formula (I).

This application claims priority to U.S. Provisional Application No.60/570,397 filed on May 12, 2004, the complete disclosure of which isherein incorporated by reference.

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates to tricyclic and bicyclic heteroaryl compounds,compositions comprising such compounds, methods for making thecompounds, and methods of treating conditions and disorders using suchcompounds and compositions.

2. Description of Related Technology

Histamine is a well-known modulator of neuronal activity. At least fourtypes of histamine receptors have been reported in the literature,typically referred to as histamine-1, histamine-2, histamine-3, andhistamine-4. The class of histamine receptor known as histamine-3receptors is believed to play a role in neurotransmission in the centralnervous system.

The histamine-3 (H₃) receptor was first characterized pharmacologicallyon histaminergic nerve terminals (Nature, 302:832–837 (1983)), where itregulates the release of neurotransmitters in both the central nervoussystem and peripheral organs, particularly the lungs, cardiovascularsystem and gastrointestinal tract. H₃ receptors are thought to bedisposed presynaptically on histaminergic nerve endings, and also onneurons possessing other activity, such as adrenergic, cholinergic,serotoninergic, and dopaminergic activity. The existence of H₃ receptorshas been confirmed by the development of selective H₃ receptor agonistsand antagonists ((Nature, 327:117–123 (1987); Leurs and Timmerman, ed.“The History of H₃ Receptor: a Target for New Drugs,” Elsevier (1998)).

The activity at the H₃ receptors can be modified or regulated by theadministration of H₃ receptor ligands. The ligands can demonstrateantagonist, agonist or partial agonist activity. For example, H₃receptors have been linked to conditions and disorders related to memoryand cognition processes, neurological processes, cardiovascularfunction, and regulation of blood sugar, among other systemicactivities. Although various classes of compounds demonstrating H₃receptor-modulating activity exist, it would be beneficial to provideadditional compounds demonstrating activity at the H₃ receptors that canbe incorporated into pharmaceutical compositions useful for therapeuticmethods.

SUMMARY OF THE INVENTION

One aspect of the invention relates to a compound of the formula:

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,wherein:

Y, and Y′ are each independently selected from the group consisting ofCH, CF, and N;

X, X′, Z, and Z′ are each independently C or N;

one of R₁ and R₂ is selected from the group consisting of L₂R₆;

the other of R₁ and R₂ is selected from the group consisting ofhydrogen, alkyl, alkoxy, aryl, cycloalkyl, halogen, cyano, andthioalkoxy, provided that R₂ is absent when Z′ is N;

R₃ is absent when X′ is N or R₃ is selected from the group consisting ofhydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy;

R_(3a) is absent when Z is N or R_(3a) is selected from the groupconsisting of hydrogen, methyl, alkoxy, halogen, and cyano;

R_(3b) is absent when X is N or R_(3b) is selected from the groupconsisting of hydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, andthioalkoxy;

R₄ and R₅ are each independently selected from the group consisting ofalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, and (NR_(A)R_(B))alkyl, wherein R_(A) and R_(B) areeach independently selected from the group consisting of hydrogen,alkyl, acyl, and formyl; or R₄ and R₅ taken together with the nitrogenatom to which each is attached form a non-aromatic ring of the formula:

R₆ is a bicyclic or tricyclic ring, each containing at least twoheteroatoms;

R₇, R₈, R₉, and R₁₀ at each occurrence are each independently selectedfrom the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, andalkyl; or one of the pair R₇ and R₈ or the pair R₉ and R₁₀ is takentogether to form a C₃–C₆ ring, wherein 0, 1, or 2 heteroatoms selectedfrom O, N, or S replace a carbon atom in the ring;

R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selected from the groupconsisting of hydrogen, hydroxy, hydroxyalkyl, alkyl, and fluoro;

Q is selected from the group consisting of a bond, O, S, and NR₁₅;

L is —[C(R₁₆)(R₁₇)]_(n)— or —[C(R₁₆)(R₁₇)]_(p)O—;

L₂ is selected from the group consisting of a bond, —O—, —C(═O)—, —S—,—[C(R₁₈)(R₁₉)]_(q)—, —O—[C(R₁₈)(R₁₉)]_(q)—, —NH— and —N(alkyl)—;

R₁₅ is selected from the group consisting of hydrogen, alkyl, acyl,alkoxycarbonyl, amido, and formyl;

R₁₆ and R₁₇ at each occurrence are independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, and fluoro;

R₁₈ and R₁₉ at each occurrence are each independently selected from thegroup consisting of hydrogen, hydroxy, alkyl, alkoxy, and fluoro;

R_(x) and R_(y) at each occurrence are independently selected from thegroup consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino,dialkylamino, and fluoro, or one of R_(x) or R_(y) represents a covalentbond when taken together with R_(x) or R_(y) on an adjacent carbon atomsuch that a double bond is represented between the adjacent carbonatoms;

m is an integer from 1 to 5;

n is an integer from 1 to 6;

p is an integer from 2 to 6; and

q is an integer from 1 to 4;

wherein 1 or 2 of X, X′, Y, Y′, Z, and Z′ is nitrogen; provided that R₃is absent when X′ is N; R_(3a) is absent when Z is N; R₂ is absent whenZ′ is N, and R_(3b) is absent when X is N.

Another aspect of the invention relates to pharmaceutical compositionscomprising compounds of the invention. Such compositions can beadministered in accordance with a method of the invention, typically aspart of a therapeutic regimen for treatment or prevention of conditionsand disorders related to H₃ receptor activity.

Yet another aspect of the invention relates to a method of selectivelymodulating H₃ receptor activity. The method is useful for treatingand/or preventing conditions and disorders related to H₃ receptormodulation in mammals. More particularly, the method is useful forconditions and disorders related to memory and cognition processes,neurological processes, cardiovascular function, and body weight.

Processes for making compounds of the invention also are contemplated.

The compounds, compositions comprising the compounds, methods for makingthe compounds, and methods for treating or preventing conditions anddisorders by administering the compounds are further described herein.

DETAILED DESCRIPTION OF THE INVENTION

Definition of Terms

Certain terms as used in the specification are intended to refer to thefollowing definitions, as detailed below.

The term “acyl” as used herein, means an alkyl group, as defined herein,appended to the parent molecular moiety through a carbonyl group, asdefined herein. Representative examples of acyl include, but are notlimited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl,and 1-oxopentyl.

The term “acyloxy” as used herein, means an acyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of acyloxy include, but are not limited to,acetyloxy, propionyloxy, and isobutyryloxy.

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through anotheralkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxyimino” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an imino group,as defined herein. Representative examples of alkoxyimino include, butare not limited to, ethoxy(imino)methyl and methoxy(imino)methyl.

The term “alkoxysulfonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkoxysulfonyl include, but are not limited to, methoxysulfonyl,ethoxysulfonyl, and propoxysulfonyl.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylamino” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a NH group.Representative examples of alkylamino include, but are not limited to,methylamino, ethylamino, isopropylamino, and butylamino.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, methylcarbonyl,ethylcarbonyl, isopropylcarbonyl, n-propylcarbonyl, and the like.

The term “alkylsulfonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “amido” as used herein, means an amino, alkylamino, ordialkylamino group appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples of amidoinclude, but are not limited to, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, and ethylmethylaminocarbonyl.

The term “amino” as used herein, means a —NH₂ group.

The term “aryl” as used herein, means a monocyclic aromatic ring system.Representative examples of aryl include, but are not limited to, phenyl.

The aryl groups of this invention are substituted with 0, 1, 2, 3, 4, or5 substituents independently selected from acyl, acyloxy, alkenyl,alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido,carboxy, cyano, cycloalkylcarbonyl, formyl, haloalkoxy, haloalkyl,halogen, hydroxy, hydroxyalkyl, mercapto, nitro, thioalkoxy,NR_(A)R_(B), and (NR_(A)R_(B))sulfonyl.

The term “arylalkoxy” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkoxy group,as defined herein. Representative examples of arylalkoxy include, butare not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and5-phenylpentyloxy.

The term “arylalkoxycarbonyl” as used herein, means an arylalkoxy group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofarylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl and 3-phenylpropyl.

The term “carbonyl” as used herein, means a —C(═O)— group.

The term “carboxy” as used herein, means a —CO₂H group, which may beprotected as an ester group —CO₂-alkyl.

The term “cyano” as used herein, means a —CN group.

The term “cycloalkenyl” as used herein, means a monocyclic hydrocarboncontaining from 3 to 8 carbons and containing at least one carbon-carbondouble bond formed by the removal of two hydrogens. Representativeexamples of cycloalkenyl include, but are not limited to,2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and3-cyclopenten-1-yl.

The term “cycloalkyl” as used herein, means a saturated cyclichydrocarbon group containing from 3 to 8 carbons. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl.

The cycoalkyl groups of the invention are substituted with 0, 1, 2, 3,or 4 substituents selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkyl, alkynyl,amido, carboxy, cyano, ethylenedioxy, formyl, haloalkoxy, haloalkyl,halogen, hydroxy, hydroxyalkyl, methylenedioxy, thioalkoxy, and—NR_(A)R_(B).

The term “cycloalkylalkyl” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cycloalkylalkylinclude, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term “cycloalkylcarbonyl” as used herein, means a cycloalkyl group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofcycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, and cycloheptylcarbonyl.

The term “dialkylamino” as used herein, means two independent alkylgroups, as defined herein, appended to the parent molecular moietythrough a nitrogen atom. Representative examples of dialkylaminoinclude, but are not limited to, dimethylamino, diethylamino,ethylmethylamino, butylmethylamino.

The term “ethylenedioxy” as used herein, means a —O(CH₂)₂O— groupwherein the oxygen atoms of the ethylenedioxy group are attached to theparent molecular moiety through one carbon atom forming a five-memberedring or the oxygen atoms of the ethylenedioxy group are attached to theparent molecular moiety through two adjacent carbon atoms forming asix-membered ring.

The term “fluoro” as used herein means —F.

The term “fluoroalkyl” as used herein, means at least one fluoro group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative example of fluoroalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, and 2,2,2-trifluoroethyl.

The term “formyl” as used herein, means a —C(O)H group.

The term “halo” or “halogen” as used herein, means Cl, Br, I, or F.

The term “haloalkoxy” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl,” as used herein, refers to an aromatic five- orsix-membered ring wherein 1, 2, 3, or 4 heteroatoms are independentlyselected from nitrogen, oxygen, or sulfur, or a tautomer thereof.Examples of such rings include, but are not limited to, a ring whereinone carbon is replaced with an O or S atom; one, two, or three N atomsarranged in a suitable manner to provide an aromatic ring, or a ringwherein two carbon atoms in the ring are replaced with one O or S atomand one N atom. The heteroaryl groups are connected to the parentmolecular moiety through a carbon or nitrogen atom. Representativeexamples of heteroaryl include, but are not limited to, furyl,imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridazinonyl, pyridinyl, pyridinonyl,pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl orthiophenyl, triazinyl, and triazolyl.

The heteroaryl groups of the invention are substituted with 0, 1, 2, 3,or 4 substituents independently selected from acyl, acyloxy, alkenyl,alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido,carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, mercapto, nitro, thioalkoxy, —NR_(A)R_(B),(NR_(A)R_(B))carbonyl, and (NR_(A)R_(B))sulfonyl.

The term “heterocycle,” as used herein, refers to a three-, four-,five-, six-, seven-, or eight-membered monocyclic ring containing one,two, or three heteroatoms independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. Rings containing at leastfour members can be saturated or unsaturated. For example, the four- andfive-membered ring has zero or one double bond. The six-membered ringhas zero, one, or two double bonds. The seven-and eight-membered ringshave zero, one, two, or three double bonds. The heterocycle groups ofthe invention can be attached to the parent molecular moiety through acarbon atom or a nitrogen atom. Representative examples ofnitrogen-containing heterocycles include, but are not limited to,azepanyl, azetidinyl, aziridinyl, azocanyl, morpholinyl, piperazinyl,piperidinyl, pyrrolidinyl, pyrrolinyl, dihydrothiazolyl, andthiomorpholinyl. Representative examples of non-nitrogen containingheterocycles include, but are not limited to, tetrahydrofuryl andtetrahydropyranyl.

The heterocycles of the invention are substituted with 0, 1, 2, 3, or 4substituents independently selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl,alkyl, alkylsulfonyl, alkynyl, amido, arylalkyl, arylalkoxycarbonyl,carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, mercapto, nitro, oxo, thioalkoxy, —NR_(A)R_(B), and(NR_(A)R_(B))sulfonyl.

The term “hydroxy” as used herein means a —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-methyl-2-hydroxyethyl, 3-hydroxypropyl,2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

The term “hydroxy-protecting group” means a substituent which protectshydroxyl groups against undesirable reactions during syntheticprocedures. Examples of hydroxy-protecting groups include, but are notlimited to, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)ethoxymethyl, benzyl, triphenylmethyl,2,2,2-trichloroethyl, t-butyl, trimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, methylene acetal, acetonide benzylidene acetal,cyclic ortho esters, methoxymethylene, cyclic carbonates, and cyclicboronates. Hydroxy-protecting groups are appended onto hydroxy groups byreaction of the compound that contains the hydroxy group with a base,such as triethylamine, and a reagent selected from an alkyl halide,alkyl trifilate, trialkylsilyl halide, trialkylsilyl triflate,aryldialkylsilyltriflate, or an alkylchloroformate, CH₂I₂, or adihaloboronate ester, for example with methyliodide, benzyl iodide,triethylsilyltriflate, acetyl chloride, benzylchloride, ordimethylcarbonate. A protecting group also may be appended onto ahydroxy group by reaction of the compound that contains the hydroxygroup with acid and an alkyl acetal.

The term “imino” as defined herein means a —C(═NH)— group.

The term “mercapto” as used herein, means a —SH group.

The term “methylenedioxy” as used herein, means a —OCH₂O— group whereinthe oxygen atoms of the methylenedioxy are attached to the parentmolecular moiety through two adjacent carbon atoms.

The term “—NR_(A)R_(B)” as used herein, means two groups, R_(A) andR_(B), which are appended to the parent molecular moiety through anitrogen atom. R_(A) and R_(B) are independently selected from hydrogen,alkyl, acyl and formyl. Representative examples of —NR_(A)R_(B) include,but are not limited to, amino, dimethylamino, methylamino, acetylamino,and acetylmethylamino.

The term “(NR_(A)R_(B))alkyl” as used herein, means an —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples of(NR_(A)R_(B))alkyl include, but are not limited to,2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 2-(amino)ethyl,2-(ethylmethylamino)ethyl, and the like.

The term “(NR_(A)R_(B))carbonyl” as used herein, means an —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofNR_(A)R_(B))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl,(ethylmethylamino)carbonyl, and the like.

The term “(NR_(A)R_(B))sulfonyl” as used herein, means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NR_(A)R_(B))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl and(ethylmethylamino)sulfonyl.

The term “nitro” as used herein means a —NO₂ group.

The term “nitrogen protecting group” as used herein, means those groupsintended to protect a nitrogen atom against undesirable reactions duringsynthetic procedures. Nitrogen protecting groups comprise carbamates,amides, N-benzyl derivatives, and imine derivatives. Preferred nitrogenprotecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz),formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc),tert-butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl).Nitrogen-protecting groups are appended onto primary or secondary aminogroups by reacting the compound that contains the amine group with base,such as triethylamine, and a reagent selected from an alkyl halide, analkyl trifilate, a dialkyl anhydride, for example as represented by(alkyl-O)₂C═O, a diaryl anhydride, for example as represented by(aryl-O)₂C═O, an acyl halide, an alkylchloroformate, or analkylsulfonylhalide, an arylsulfonylhalide, or halo-CON(alkyl)₂, forexample acetylchloride, benzoylchloride, benzylbromide,benzyloxycarbonylchloride, formylfluoride, phenylsulfonylchloride,pivaloylchloride, (tert-butyl-O—C═O)₂O, trifluoroacetic anhydride, andtriphenylmethylchloride.

The term “oxo” as used herein means (═O).

The term “bicyclic ring” as used herein, refers to a bicyclic aryl, asdefined herein, a bicyclic heteroaryl, as defined herein, or a bicyclicheterocycle, as defined herein.

The term “tricyclic ring” as used herein, refers to a tricyclicheteroaryl, as defined herein, or a tricyclic heterocycle, as definedherein.

The bicyclic and tricyclic ring systems of the present invention aresubstituted with 0, 1, 2, 3, or 4 substituents independently selectedfrom acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl,alkynyl, amido, arylalkyl, arylalkoxycarbonyl, carboxy, cyano, formyl,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro,oxo, thioalkoxy, —NR_(A)R_(B), and (NR_(A)R_(B))sulfonyl.

It is also contemplated that the nitrogen heteroatoms in the monocyclic,bicyclic and tricyclic ring systems can be optionally quaternized oroxidized to the N-oxide. Also, the nitrogen containing heterocyclicrings can be optionally N-protected.

The term “bicyclic aryl” as used herein, refers to a bicyclic fused ringsystem wherein a phenyl group is fused to a monocyclic heterocyclegroup, as defined herein. Representative examples of bicyclic arylgroups include, but are not limited to, benzo[1,3]dioxolyl, andbenzo[1,3]dioxinyl. The bicyclic aryl groups are connected to the parentmoiety through any substitutable carbon or nitrogen atoms of the group.

The term “bicyclic heteroaryl” as used herein, refers to a bicyclicfused ring system where a heteroaryl ring, as defined herein is fused toa phenyl group, a monocyclic cycloalkyl group, as defined herein, amonocyclic cycloalkenyl group, as defined herein, a heterocycle group,as defined herein, or an additional heteroaryl group. The bicyclicheteroaryl groups are connected to the parent molecular moiety throughany substitutable carbon or nitrogen atom of the groups. Examples ofbicyclic heteroaryl groups include, but are not limited to,benzothiazolyl, benzoxadiazolyl, benzotriazolyl, indazolyl,isothiazolyl, 4H-thieno[3,2,b]pyrrolyl, imidazo[1,2-a]pyridin-3-yl,[1,2,4]triazolo[1,5-a]pyrimidin-5-yl, [1,3]dioxolo[4,5-b]pyridin-6-yl,thiazolo[3,2-b][1,2,4]triazol-5-yl,2,3-dihydro-imidazo[2,1-b]thiazol-6-yl, pyrazolo[1,5-a]pyrimidin-6-yl,and naphthyridinyl.

The term “tricyclic heteroaryl” as used herein, refers to a tricyclicfused ring system where a bicyclic heteroaryl, as defined herein, isfused to a phenyl group, a monocyclic cycloalkenyl group, as definedherein, a monocyclic cycloalkyl group, as defined herein, a heterocyclegroup, as defined herein, or an additional heteroaryl group. Thetricyclic heteroaryl groups are connected to the parent molecular moietythrough any substitutable carbon or nitrogen atom of the groups.Examples of tricyclic heteroaryl groups include, but are not limited to,benzo[4,5]imidazo[2,1-b]thiazolyl.

The term “bicyclic heterocyle” as used herein, refers to a bicyclicfused ring system where a heterocycle ring is fused to a monocycliccycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, asdefined herein, or an additional monocyclic heterocycle group, asdefined herein. The bicyclic heterocycle groups are connected to theparent molecular moiety through any substitutable carbon or nitrogenatom of the groups. Representative examples of bicyclic heterocyclesinclude, but are not limited to, octahydro-pyrrolo[3,4-c]pyrrolyl;octahydro-pyrido[1,2-a]pyrazinyl;3-thioxo-hexahydro-pyrrolo[1,2-c]imidazol-1-one;tetrahydro-imidazo[4,5-d]imidazole-2,5-dione;hexahydro-pyrrolo[1,2-a]pyrazine-1,4-dione;hexahydro-pyrano[3,4-c]pyrrol-4-one;3-thioxo-hexahydro-pyrrolo[1,2-c]imidazol-1-one;decahydro-pyrazino[2,3-b]pyraziinyl;hexahydro-pyrido[1,2-a]pyrazin-1-one; hexahydro-furo[3,4-c]pyrrol-1-one;hexahydro-thieno[3,4-c]pyrrol-1-one; octahydro-benzoimidazol-2-one;hexahydro-pyrrolo[1,2-a]pyrazine-1,4-dione;octahydro-pyrrolo[3,4-b]pyridinyl;tetrahydro-[1,4]dithiino[2,3-c]pyrrole-5,7-dione;hexahydro-pyrrolo[1,2-c]imidazole-3-thione;hexahydro-pyrrolo[1,2-c]imidazole-3-thione;tetrahydro-thieno[3,4-d]imidazol-2-one; andoctahydro-pyrrolo[1,2-a]pyrazinyl.

The term “tricyclic heterocycle” as defined herein, refers to atricyclic fused ring system where a bicyclic heterocycle, as definedherein, is fused to a monocyclic cycloalkenyl group, as defined herein,a monocyclic cycloalkyl group, as defined herein, or an additionalmonocyclic heterocycle group, as defined herein. The tricyclicheterocycle groups are connected to the parent molecular moiety throughany substitutable carbon or nitrogen atom in the groups. Representativeexamples of tricyclic heterocycles include, but are not limited to,hexahydro-1-oxa-2a,3-diaza-cyclopenta[cd]pentalen-2-one anddodecahydro-1,4,7,9b-tetraaza-phenalene.

The term “sulfonyl” as used herein means a —S(O)₂— group.

The term “thioalkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of thioalkoxy include, but are no limited to,methylthio, ethylthio, and propylthio.

As used herein, the term “antagonist” encompasses and describescompounds that prevent receptor activation by an H₃ receptor agonistalone, such as histamine, and also encompasses compounds known as“inverse agonists”. Inverse agonists are compounds that not only preventreceptor activation by an H₃ receptor agonist, such as histamine, butalso inhibit intrinsic H₃ receptor activity.

Compounds of the Invention

Compounds of the invention can have the general formula (I) as describedabove.

The invention also includes compounds having the formula (I) wherein Yand Y′ are CH; X, X′, and Z′ are C; R₂, R₃, and R_(3b) are hydrogen; Zis N; and R_(3a) is absent.

In another embodiment, compounds of the invention can have formula (I)wherein Y is CH; X, X′, Z, and Z′ are C; R₂, R₃, R_(3a), and R_(3b) arehydrogen; and Y′ is N.

In yet another embodiment, compounds of the invention have formula (I)wherein Y and Y′ are CH; X and Z′ are C; R₂ and R_(3b) are hydrogen; X′is N; Z is N; and R₃ and R_(3a) are absent.

Yet another embodiment relates to compounds of the invention having theformula (I) wherein X, X′, Z, and Z′ are C; R₂, R₃, R_(3a), and R_(3b)are hydrogen; Y is N; and Y′ is N.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y′ is CH; X, X′, and Z are C; R₃, R_(3a),and R_(3b) are hydrogen; Y is N; Z′ is N; and R₂ is absent.

Another embodiment relates to compounds of the invention having theformula (I) wherein Y′ is CH; X, Z, and Z′ are C; R₂, R_(3a), and R_(3b)are hydrogen; Y is N; X′ is N; and R₃ is absent.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y′ is CH; X, X′, and Z′ are C; R₂, R₃,and R_(3b) are hydrogen; Y is N; Z is N; and R_(3a) is absent.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y is CH; X, X′, and Z are C; R₃, R_(3a),and R_(3b) are hydrogen; Y′ is N; Z′ is N; and R₂ is absent.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y and Y′ are CH; Z′ and Z are C; R₂ andR_(3a) are hydrogen; X′ is N; X is N; and R₃ and R_(3b) are absent.

Compounds of the invention also can have the formula (I) wherein Y′ isCH; X, X′, Z and Z′ are C; R₂, R₃, R_(3a), and R_(3b) are hydrogen; andY is N.

In yet another embodiment, compounds of the invention have formula (I)wherein Y and Y′ are CH; X′ and Z′ are C; R₂ and R₃ are hydrogen; X isN; Z is N; and R_(3a) and R_(3b) are absent.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y is CH; X, Z′, and Z are C; R₂, R_(3a),and R_(3b) are hydrogen; Y′ is N; X′ is N; and R₃ is absent.

Preferred compounds of the invention are those compounds of formula (I)wherein Y′ is CH; X, X′, Z and Z′ are C; R₂, R₃, R_(3a), and R_(3b) arehydrogen; and Y is N.

R₁ can be any tricyclic or bicyclic ring attached either directly to theheteroaryl core or via a linker as defined by L₂, wherein L₂ is a bond,—O—, —C(═O)—, —S—, —[C(R₁₈)(R₁₉)]_(q)—, —O—[C(R₁₈)(R₁₉)]_(q)—, —NH— and—N(alkyl)—. Suitably tricyclic and bicyclic rings contain at least twoheteroatoms. Preferred tricyclic and bicyclic rings have from two tofour heteroatoms. Preferably, compounds of the invention are thosewherein R₁ is L₂R₆, L₂ is —CH₂— or a bond, and R₆ is an aromatic ornon-aromatic 5- to 6-membered ring fused to an aromatic or non-aromatic5- to 10-membered ring, provided that the fused system contains at leasttwo heteroatoms. It is preferred that L₂ is a bond.

Specific examples of R₆ include, but are not limited to,4H-thieno[3,2-b]pyrrolyl; benzo[4,5]imidazo[2,1-b]thiazolyl;2-methyl-imidazo[1,2-a]pyridinyl; 4H-benzo[1,3]dioxinyl;[1,2,4]triazolo[1,5-a]pyrimidinyl; benzothiazolyl; benzotriazolyl;[1,3]dioxolo[4,5-b]pyridinyl; 6-methyl-thiazolo[3,2-b][1,2,4]triazolyl;2,3-dihydro-imidazo[2,1-b]thiazolyl;2,7-dimethyl-pyrazolo[1,5-a]pyrimidinyl; [1,8]naphthyridinyl; andquinoxalinyl.

Other bicyclic and tricyclic rings suitable for R₆ are:

and the like. Such rings can be attached to the parent molecular moietythrough a group L₂, as previously described, via any suitable carbonatom.

Preferably, R₄ and R₅ are taken together with the nitrogen atom to whicheach is attached form a 4- to 8-membered non-aromatic ring representedby formula (a). The preferred compounds of the invention are thosewherein at least one substituent represented by R₇, R₈, R₉, and R₁₀ isselected from the group consisting of alkyl, halogen, fluoroalkyl, andhydroxyalkyl or at least one substituent represented by R_(x) or R_(y)is selected from the group consisting of hydrogen, hydroxy, and fluoro.More preferably, R₄ and R₅ taken together with the nitrogen atom towhich each is attached to form 2-methylpyrrolidine and, morespecifically, (2R)-methylpyrrolidine.

Specific compounds contemplated as part of the invention include, butare not limited to, for example:

-   6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-(4H-thieno[3,2-b]pyrrol-5-yl)-quinoline;-   3-methyl-2-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-benzo[4,5]imidazo[2,1-b]thiazole;-   2-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   2-(4H-benzo[1,3]dioxin-6-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl-quinoline;-   2-benzothiazol-2-yl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   3-benzotriazol-1-ylmethyl-2-methyl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   2-[1,3]dioxolo[4,5-b]pyridin-6-yl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-2-(6-methyl-thiazolo[3,2-b][1,2,4]triazol-5-yl)-quinoline;-   2-(2,3-dihydro-imidazo[2,1-b]thiazol-6-yl)-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline;-   2-(2,7-dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl)-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline;-   2-methyl-3-{6-[2-([2R]-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-[1,8]naphthyridine;-   6-{6-[2-([2R]-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-quinoxaline;-   6-(2-methyl-benzothiazol-5-yl)-2-[2-(2R-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;    and-   7-(2-methyl-benzothiazol-5-yl)-3-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-isoquinoline.

Compounds of the invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13–30. The inventioncontemplates various stereoisomers and mixtures thereof and these arespecifically included within the scope of this invention. Stereoisomersinclude enantiomers and diastereomers, and mixtures of enantiomers ordiastereomers. Individual stereoisomers of compounds of the inventionmay be prepared synthetically from commercially available startingmaterials which contain asymmetric or chiral centers or by preparationof racemic mixtures followed by resolution well-known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and optional liberation of theoptically pure product from the auxiliary as described in Furniss,Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical OrganicChemistry”, 5th edition (1989), Longman Scientific & Technical, EssexCM20 2JE, England, or (2) direct separation of the mixture of opticalenantiomers on chiral chromatographic columns or (3) fractionalrecrystallization methods.

Methods for Preparing Compounds of the Invention

The compounds of the invention can be better understood in connectionwith the following synthetic schemes and methods which illustrate ameans by which the compounds can be prepared.

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are: Ac for acetyl; atm for atmosphere(s);BINAP for 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc forbutyloxycarbonyl; Bu for butyl; dba for dibenzylidene acetone; DCM fordichloromethane; DMAP for 4-(N,N-dimethylamino)pyridine; DMF forN,N-dimethylformamide; DMSO for dimethylsulfoxide; dppf for1,1′-bis(diphenylphosphino)ferrocene; Et for ethyl; EtOH for ethanol;EtOAc for ethyl acetate; HPLC for high pressure liquid chromatography;IPA for isopropyl alcohol; IPAC or IPAc for isopropyl acetate; LAH forlithium aluminum hydride; LDA for lithium diisopropylamide; NBS forN-bromosuccinimide; NIS for N-iodosuccinimide; Me for methyl; MeOH formethanol; Ms for methanesulfonyl; MTBE for tert-butyl methyl ether; Pdfor palladium; tBu for tert-butyl; TBDMSCl for t-butyldimethylsilylchloride; TBDMSO for t-butyldimethylsilyl-O; TEA for triethylamine; TFAfor trifluoroacetic acid; THF for tetrahydrofuran; TMEDA forN,N,N′,N′-tetramethylethylenediamine; TfO for CF₃S(O)₃—; and Ts forp-MePhS(O)₂—.

The compounds of this invention can be prepared by a variety ofsynthetic procedures. Representative procedures are shown in, but arenot limited to, Schemes 1–27.

Compounds of formula (7) and (9), wherein X, X′, Y, Y′, Z, Z′, R₂, R₃,R₄, R₅, R₆, and L₂ are as defined in formula (I), can be prepared asdescribed in Scheme 1. Compounds of formula (1), wherein W is OH, Br,Cl, or I, purchased or prepared using methodolgy known to those ofordinary skill in the art, can be treated with lithium diisopropylamineand a chloroformate such as, but not limited to, ethyl chloroformate toprovide esters of formula (2). Esters of formula (2) can be treated witha reducing agent such as, but not limited to, lithium borohydride toprovide alcohols of formula (3). Alcohols of formula (3) wherein W isBr, Cl, or I can be treated with a base such as, but not limited to,triethylamine and a sulfonating agent such as, but not limited to,methanesulfonyl chloride or p-toluensulfonyl chloride to providesulfonates of formula (4). Compounds of formula (3) wherein W is —OH canbe converted to compounds of formula (4a) wherein W is triflate byreaction with triflic anhydride and a base such as, but not limited to,pyridine or triethylamine. Sulfonates or triflates of formula (4) or(4a) can be treated with an optional base such as, but not limited to,potassium carbonate or sodium carbonate and an amine of formula (5) withor without heat to provide amines of formula (6), wherein W is triflate,Br, Cl, or I.

The Suzuki reaction can be used to produce compounds of formula (7),wherein L₂ is a bond, and X, X′, Y, Y′, Z, Z′, R₂, R₃, R₄, R₆ and R₅ areas defined for formula (I). In such a Suzuki reaction, compounds offormula (6) wherein W is triflate, Br, Cl, or I are reacted with boronicacids of formula (14), as shown in Scheme 4 herein, wherein R₉₄ ishydrogen, a metal catalyst, a base, and optionally with a Pd ligandadded. The reaction can be performed in a solvent such as, but is notlimited to, tetrahydrofuran, DMF, 1,4-dioxane and the like, at atemperature from about 20° C. to about 120° C. Examples of metalcatalysts include, but are not limited to, palladium diacetate,Pd(PPh₃)₄, Pd₂(dba)₃, dichloro(di-tert-butylphosphinous acid) palladium(II) dimmer, and PdCl₂(dppf). Examples of bases include, but are notlimited to, 0.2 M K₃PO₄, Cs₂CO₃, CsF, KF, and Na₂CO₃. Examples ofpalladium ligands include, but are not limited to,(dicyclohexylphosphinyl)biphenyl, trifurylphosphine, tris(tert-butyl)phosphine, and triphenylphosphine. Boronic acid esters of formula (14)wherein R₉₄ is alkyl, and L₂ is a bond can be used in place of boronicacids in the aforesaid reaction. Boronic acids can be esterified to thecorresponding boronic acid esters with alcohols such as methanol or withdiols such as pinacol.

There are many aryl or heteroaryl boronic acids and boronic acid estersthat are available commercially or that can be prepared as described inthe scientific literature of synthetic organic chemistry.

Alternatively, using the Stille coupling, compounds of formula (7)wherein L₂ is a bond, and X, X′, Y, Y′, Z, Z′, R₂, R₃, R₄, R and R₅, areas defined for formula (I), may be prepared from compounds of formula(6) wherein W is triflate, Cl, Br, or I, by treatment with aryl orheteroaryl stannanes of formula (13), as shown in Scheme 4 herein, apalladium source such as tris(dibenzylidineacetone)dipalladium (CAS #52409-22-0) or palladium diacetate, and a ligand such astri(2-furyl)phosphine (CAS # 5518-52-5) or triphenyl arsine in asolvent, for example in DMF at a temperature from about 25° C. to about150° C. While many organotin reagents for the Stille coupling arecommercially available or described in the literature, new organotinreagents can be prepared from arylhalides, aryltriflates,heteroarylhalides, heteroaryltriflates by reaction with distannanes like(Me₃Sn)₂ (hexamethyl distannane) in the presence of a palladium sourcelike Pd(Ph₃P)₄. Such methods are described, for instance, in Krische,et. al., Helvetica Chimica Acta 81(11):1909–1920 (1998), and inBenaglia, et al., Tetrahedron Letters 38:4737–4740 (1997). Thesereagents can be reacted with (6) wherein W is triflate, Cl, Br, or I, togive (7) wherein L₂ is a bond, and X, X′, Y, Y′, Z, Z′, R₂, R₃, R₄, R₅and R₆ are as defined in formula (I), as described under Stilleconditions, or for example under the conditions reported by Littke,Schwartz, and Fu, Journal of the American Chemical Society 124:6343–6348(2002).

Alternatively, compounds of formula (7) wherein L₂ is a bond or—[C(R₁₈)(R₁₉)]_(q)—, and X, X′, Y, Y′, Z, Z′, R₂, R₃, R₄, R₅ and R₆ areas defined for formula (I), can be prepared according to the so calledNegishi coupling by reaction of a compound of formula (6) wherein W is ahalide or triflate, with a compound of the formula halide-zinc-L₂R₆. Thecatalyst may be selected from those typically employed for the reaction(for example, tetrakis(triphenylphosphine)palladium,tetrakis(triphenylphosphine)nickel,dichlorobis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium/n-butyl lithium,dichlorobis(1,1-bis(diphenylphosphino)ferrocene)palladium anddichlorobis(1,4-bis(diphenylphosphino)butane)palladium). Suitablesolvents include tetrahydrofuran, diethylether and dimethoxyethane. Thereaction is typically carried out at a temperature from about 20° C. toabout 160° C., usually 20° C. to 130° C. for 10 minutes to about 5 days,usually 30 minutes to about 15 hours. Alternatively, one skilled in theart will appreciate that the reactive groups of the reagents can bereversed. Thus one skilled in the art will appreciate that W in theaforesaid reaction can be the zinc halide coupled to an R₆L₂-halide ortriflate. (Knochel, P. and Singer, R. D. Chem. Rev., 93, pages2117–2188, 1993).

Compounds of formula (7) wherein L₂ is a bond, R₆ is a heterocycle, andX, X′, Y, Y′, Z, Z′, R₂, R₃, R₄ and R₅ are as defined for formula (I),can be prepared by treating compounds of formula (6) wherein W is Br, orI, with an organolithium reagent such as, but not limited to,n-butyllithium, sec-butyllithium or tert-butyllithium to provide alithium intermediate. This lithium intermediate can then be treated witha heterocycle that is substituted with —C(═O), such as tropinone, toprovide an alcohol. An example of this transformation can be found in(Appell, M. et al. Bioorg. Med. Chem. 2002, 10, 1197–1206).Alternatively, compounds of formula (6) wherein W is Br, or I, can beconverted into a Grignard reagent and reacted with a heterocycle that issubstituted with —C(═O), such as tropinone, to provide an alcohol. Theresulting alcohol can be optionally eliminated to the correspondingalkene via methods known to those of ordinary skill in the art toprovide the corresponding alkene. The double bond of the alkene can beoptionally reduced to the saturated bond by methods known to those ofordinary skill in the art.

Compounds of formula (7) wherein L₂ is a bond, R₆ is anitrogen-containing heteroaryl or heterocycle ring linked to thebicyclic core group through a nitrogen, and X, X′, Y, Y′, Z, Z′, R₂, R₃,R₄ and R₅ are as defined for formula (I), may be prepared by heatingcompounds of formula (6) wherein W is triflate or halogen, with acompound of the formula H—R₆ wherein H is a hydrogen on a nitrogen atom,with a base such as, but not limited to, sodium t-butoxide or cesiumcarbonate, in the presence of a metal catalyst such as, but not limitedto, copper metal or CuI, palladium diacetate, and also optionally with aligand such as, but not limited to, BINAP, tri-tertbutylphosphine in asolvent such as dioxane, toluene, N,N-dimethylformamide (DMF),N,N-dimethylacetamide, N-methylpyrrolidinone (NMP) or pyridine.References that describe these methodologies may be found in thefollowing references: J. Hartwig et al., Angew. Chem. Int. Ed.37:2046–2067 (1998); J. P. Wolfe et al., Acc. Chem. Res., 13:805–818(1998); M. Sugahara et al., Chem. Pharm. Bull., 45:719–721 (1997); J. P.Wolfe et al., J. Org. Chem., 65:1158–1174, (2000); F. Y. Kwong et al.,Org. Lett., 4:581–584, (2002); A. Klapars et al., J. Amer. Chem. Soc.,123:7727–7729 (2001); B. H. Yang et al., J. Organomet. Chem.,576:125–146 (1999); A. Kiyomori et al., Tet. Lett., 40:2657–2640 (1999);and Hartwig, J. Org. Chem., 64(15):5575–5580 (1999).

Compounds of formula (6) wherein W is Br, or I, can also be treated withan organolithium reagent such as, but not limited to, n-butyllithium,sec-butyllithium or tert-butyllithium to provide an intermediate anionwhich is then reacted with an amide of formula (8) to provide compoundsof formula (9) wherein X, X′, Y, Y′, Z, Z′, R₂, R₃, R₄, R₅ and R₆ are asdefined for formula (I). Compound (8) is prepared from the correspondingcarboxylic acid of formula R₆—COOH via activation (with SOCl₂, oxalylchloride, N,N′-carbonyl diimidazole (CDI),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), or EtOCCI) andsubsequent reaction with N,O-dimethylhydroxylamine in the presence of anon-nucleophilic base.

Compounds of formula (7) wherein L₂ is —NH— or —N(alkyl)—and X, X′, Y,Y′, Z, Z′, R₂, R₃, R₄, R₅, and R₆ are as defined for formula (I) can beprepared by heating compounds of formula (6) wherein W is triflate orhalogen, with compounds of formula H₂N—R₆, or HN(alkyl)—R₆, with a basesuch as, but not limited to sodium tert-butoxide or cesium carbonate, inthe presence of a metal catalyst such as, but not limited to, coppermetal or CuI, palladium diacetate, and also optionally with a ligandsuch as, but not limited to, BINAP, tri-tertbutylphosphine in solventssuch as dioxane, toluene, pyridine. References that describe thesemethodologies may be found in the following references: J. Hartwig, etal., Angew. Chem. Int. Ed., 37:2046–2067 (1998); J. P. Wolfe et al.,Acc. Chem. Res., 13:805–818 (1998); J. P. Wolfe et al., J. Org. Chem.,65:1158–1174 (2000); F. Y. Kwong et al., Org. Lett., 4:581–584, (2002);B. H. Yang et al., J. Organomet. Chem., 576:125–146 (1999); and Hartwig,J. Org. Chem., 64(15):5575–5580 (1999).

Compounds of formula (7), wherein L₂ is oxygen, and X, X′, Y, Y′, Z, Z′,R₂, R₃, R₄, R₅, and R₆ are as defined for formula (I) can be prepared byheating compounds of formula (6) wherein W is triflate or halogen, witha compound of formula HOR₆ wherein R₆ is as defined in formula (I),using a base such as but not limited to sodium hydride in a solvent suchas toluene or N,N-dimethylformamide, in the presence of a metalcontaining catalyst such as CuI or palladium diacetate. References thatdescribe these methodologies may be found in the following references:J. Hartwig et al., Angew. Chem. Int. Ed., 37:2046–2067 (1998); J.-F.Marcoux et al., J. Am. Chem. Soc., 119:10539–10540 (1997); A. Aranyos etal., J. Amer. Chem. Soc., 121:4369–4378 (1999); M. Palucki et al., J.Amer. Chem. Soc., 119:3395–3396 (1997); and T. Yamamoto et al., Can. J.Chem., 61:86–91 (1983). Additional methodologies useful for thesynthesis of compounds of formula (7), wherein L₂ is oxygen and R₆ is asdefined in formula (1) can be found in the following references: A.Aranyos et al., J. Amer. Chem. Soc., 121:4369–4378 (1999); E. Baston etal., Synth. Commun., 28:2725–2730 (1998); and A. Toshimitsu et al., Het.Chem., 12:392–397 (2001).

Compounds of formula (7), wherein L₂ is sulfur and X, X′, Y, Y′, Z, Z′,R₂, R₃, R₄, R₅, and R₆ are as defined for formula (I) can be prepared byheating compounds of formula (6) wherein W is halogen with a compound offormula HSR₆, wherein R₆ is as defined for formula (I), using a basewith or without a metal catalyst such as CuI or palladium diacetate, inthe presence of a base in a solvent such as dimethylformamide ortoluene. References that describe these methodologies may be found inthe following references: G. Y. Li et al., J. Org. Chem., 66:8677–8681(2001); G. Y. Li et al., Angew. Chem. Int. Ed., 40:1513–1516 (2001); U.Schopfer et al., Tetrahedron, 57:3069–3074 (2001); and C. Palomo et al.,Tet. Lett., 41:1283–1286(2000).

Compounds of formula (7), wherein L₂ is —O[C(R₁₈)(R₁₉)]_(q)—, and X, X′,Y, Y′, Z, Z′, R₂, R₃, R₄, R₅, R₆, q, R₁₈, and R₁₉ are as defined forformula (I) can be prepared by treating compounds of formula (6) whereinW is OH with a compounds of formula HO[C(R₁₈)(R₁₉)]_(q)R₆ wherein R₆, q,R₁₈, and R₁₉ are as defined for formula (I), in the presence of diethylazodicarboxylate and triphenylphosphine using the conditions of theMitsunobu reaction which is well known to one skilled in the art oforganic chemistry. Compounds of formula (6) wherein W is OH can begenerated from compounds of formula (6) wherein W is Cl, Br or I asdescribed in Mann, G.; et. al. J. Amer. Chem. Soc. 1999, 121, 3224–3225.Alternatively, compounds of formula (7), wherein L₂ is—O[C(R₁₈)(R₁₉)]_(q)—, and X, X′, Y, Y′, Z, Z′, R₂, R₃, R₄, R₅, R₆, q,R₁₈, and R₁₉, are as defined for formula (I) can be prepared by heatingcompounds of formula (6) wherein W is Cl, Br or I with compounds offormula HO[C(R₁₈)(R₁₉)]_(q)R₆ wherein R₆, q, R₁₈, and R₁₉ are as definedin formula (I), in the presence of a base such as Cs₂CO₃ and a catalystsuch as Pd(OAc)₂ in a solvent such as toluene or DMF (Torraca, K. E.;et. al. J. Amer. Chem. Soc. 123, 2001, 10770–10771.)

Compounds of formula (7), wherein L₂ is —[C(R₁₈)(R₁₉)]_(q)—, q is 1, andX, X′, Y, Y′, Z, Z′, R₂, R₃, R₄, R₅, R₆, R₁₈ and R₁₉ are as defined forformula (I), can be prepared from compounds of formula (9). Compounds offormula (9) can be manipulated by reactions well known to those skilledin the art of organic chemistry such as the Grignard reaction, catalytichydrogenation, metal hydride reduction, alkylation of alcohols,fluorination with (diethylamino)sulfur trifluoride, fluorination with[bis(2-methoxyethyl)amino]sulfur trifluoride to provide compounds offormula (7), wherein L₂ is —[C(R₁₈)(R₁₉)]_(q)—, q is 1, and X, X′, Y,Y′, Z, Z′, R₂, R₃, R₄, R₅, R₆, R₁₈, and R₁₉, are defined for formula(I).

Compounds of formula (7), wherein L₂ is —[C(R₁₈)(R₁₉)]_(q)— and X, X′,Y, Y′, Z, Z′, R₂, R₃, R₄, R₅, R₆, R₁₈, R₁₉ and q are as defined forformula (I) can be prepared by cross-coupling reactions known to thoseskilled in the art. Examples of these reactions are the Kumada, Suzuki,Heck, Stille, Suzuki-Miyaaura, Tamao-Kamuda and Sonogashira reaction.Suitable reagents, for example, alkyl Grignard reagents, boronic acidsor ester, tin intermediates, alkenes and alkynes can be coupled withcompounds of formulas (6) wherein W is triflate or halogen, in thepresence of a metal catalyst such as palladium, nickel, silver orindium, to prepare compounds of formula (7), wherein L₂ is a substitutedor unsubstituted alkyl, alkenyl or alkynyl chain. Compounds of formula(7) wherein L₂ is an alkenyl or alkynyl chain can be reduced tocompounds of formula (7) wherein L₂ is an alkyl chain by methods knownto those skilled in the art such as catalytic hydrogenation. Referencesthat describe these methodologies are: G. A. Molander et al.,Tetrahedron, 58:1465–1470 (2002); W. Dohle et. al., Org. Lett.,3:2871–2873 (2001); G. Zou et al., Tet. Lett., 42:7213–7216 (2001); A.J. Suzuki, Organomet. Chem., 576:147–168 (1999); A. F. Littke, J. Amer.Chem. Soc., 122:4020–4028 (2000); N. Miyaura et al., Chem. Rev.,95:2457–2483 (1995); H. Horie et al., J. Mater. Chem., 11:1063–1071(2001); C. Dai et al., J. Amer. Chem. Soc., 123:2719–2724 (2001); F.Diederich et al., Metal-catalyzed Cross-Coupling Reactions, Wiley-VCH;Weinheim, 1998; A. Mohanakrishnan et al., Syn. Lett., 7:1097–1099(1999); B. H. Lipshutz et al., Org. Lett., 3:1869–1872 (2001); B. H.Lipshutz et al., Tet. Lett., 40:197–200 (1999); and J. Tsuji, PalladiumReagents and Catalysts-innovations in Organic Synthesis, John Wiley &Sons: New York, 1995.

Compounds of formula (7), wherein L₂ is a bond, and X, X′, Y, Y′, Z, Z′,R₂, R₃, R₄, R₆ and R₅ are as defined in formula (I) can be prepared asdescribed in Scheme 2. Halides of formula (6) wherein W is Br, Cl, or I,can be treated with a distannane such as hexamethylditin (CAS #661-69-8) in the presence of a catalyst such as Pd(PPh₃)₄ in a solventsuch as dioxane with heating to provide tin intermediates of structure(6a), wherein R₉₁ is lower alkyl (Li, D. et. al., J. Org. Chem.,65:2802–2805 (2000)). Alternatively, compounds of formula (6) wherein Wis Br or I can be treated with an alkyllithium reagent such as sec-BuLiin a solvent such as THF or diethyl ether at −78° C. to provide anintermediate lithium species via a lithium-halogen exchange reactionfollowed by reaction with trialkyltin chloride such as tri-n-butyltinchloride to provide tin intermediates of structure (6a). Using theStille coupling reaction conditions as described in Scheme 1, tinintermediates of structure (6a) can be reacted with halides of formula(10) or triflates of structure (11) to provide compounds of formula (7)wherein L₂ is a bond, and X, X′, Y, Y′, Z, Z′, R₂, R₃, R₄, R₆ and R₅ areas defined in formula (I).

Alternatively, compounds of formula (7), wherein L₂ is a bond, and X,X′, Y, Y′, Z, Z′, R₂, R₃, R₄, R₆ and R₅ are as defined in formula (I)can be prepared as described in Scheme 3. Compounds of formula (6)wherein W is Br or I can be treated with an alkyllithium reagent such assec-BuLi in a solvent such as THF or diethyl ether at −78° C. to providean intermediate lithium species via a lithium-halogen exchange reactionfollowed by a trialkoxyborate such as triiosopropyl borate to provide aborate intermediate of formula (12) wherein R₉₂ is hydrogen.Alternatively, compounds of formula (6) wherein W is triflate, Br, Cl orI, can be treated with bis-(pinacolato)diboron in the presence of acatalyst such as PdCl₂(dppf) as described in Ishiyama, T.; et. al. J.Org. Chem. 1995, 60, 7508–7510 to provide borates of general structure(12) wherein B(OR₉₂)₂ is boronpinacolate. Using the Suzuki couplingreaction as described in Scheme 1, a reaction well known to thoseskilled in the art of organic chemistry, borate intermediates ofstructure (12) can be reacted with halides of structure (10) ortriflates of structure (11) to provide compounds of general structure(7) wherein L₂ is a bond, and X, X′, Y, Y′, Z, Z′, R₂, R₃, R₄, R₆ and R₅are as defined for formula (I).

Tin intermediates of formula (13) wherein R₉₃ is lower alkyl, L₂ is abond, and R₆ is defined as in formula (I), can be prepared as describedin Scheme 4 from the corresponding halides of formula (10), wherein L₂is a bond, by treatment with a distannane such as hexamethylditin (CAS #661-69-8) in the presence of a catalyst such as Pd(PPh₃)₄ in a solventsuch as dioxane with heating to provide tin intermediates of structure(13), wherein R₉₃ is lower alkyl. Alternatively, halide intermediates ofstructure (10) can be reacted with an alkyl lithium reagent such assec-BuLi to provide an intermediate lithium species which can then betreated with a tri-alkyltin chloride such as trimethyltin chloride. Anexample of this transformation can be found in Balle, T. et. al.,Synthesis, 11:1509–1512 (2002).

Boronic acid ester intermediates of formula (14), wherein R₉₄ is H orlower alkyl, L₂ is a bond, and R₆ is as defined in formula (I), can beprepared by the reaction of halides of formula (10), wherein L₂ is abond and n is 0 or 1, with an alkyllithium reagent such as sec-BuLi in asolvent such as THF or ether at −78° C. to provide an intermediatelithium species via a lithium-halogen exchange reaction followed by atrialkoxyborate such as triiosopropyl borate. Halides of structure (10)can be also treated with bis-(pinacolato)diboron in the presence of acatalyst such as PdCl₂(dppf) as described in Ishiyama, T. et. al., J.Org. Chem. 60:7508–7510 (1995) to provide borates of general structure(14), wherein B(OR₉₄)₂ is boronpinacolate, L₂ is a bond and n is 0 or 1.

Alternatively, compounds of formula (7), wherein X, X′, Y, Y′, Z, Z′,L₂, R₂, R₃, R₄, R₅ and R₆ are as defined in formula (I), can be preparedas described in Scheme 5. Esters of formula (15) can be treated with areducing agent such as, but not limited to, lithium aluminum hydride toprovide alcohols of formula (16). Alcohols of formula (16) can betreated with thionyl chloride to provide chlorides of formula (17).Chlorides of formula (17) can be treated with sodium cyanide orpotassium cyanide to provide the nitrile which can be treated withaqueous acid to provide acids of formula (18). Acids of formula (18) canbe treated with a reducing agent such as, but not limited to, diboraneor borane THF complex to provide alcohols of formula (19). Alcohols offormula (19) can be used in place of compound (3) in Scheme 1.Alternatively, alcohols of formula (19) can be treated with ahydroxy-protecting reagent such as, but not limited to,tert-butyldimethylsilyl chloride. The protected compounds of formula(20) can be processed as described in Schemes 1–3 to provide compoundsof formula (21). Compounds of formula (21) can be deprotected usingmethods known to those of ordinary skill in the art and then treatedwith a sulfonating agent such as, but not limited to, methanesulfonylchloride or p-toluensulfonyl chloride to provide sulfonates of formula(22). Sulfonates of formula (22) can be treated with an amine of formula(5) to provide compounds of formula (7).

Compounds of formula (26), wherein X, X′, Y, Y′, Z, Z′, L₂, R₂, R₃, R₄,R₅ and R₆ are as defined in formula (I), can be prepared as described inScheme 6. Hydroxy compounds of formula (23), purchased or prepared usingmethods known to those of ordinary skill in the art, can be treated with1,2-dibromoethane to provide bromides of formula (24). Bromides offormula (24) can be treated with amines of formula (5) to providecompounds of formula (25). Compounds of formula (25) can be processed asdescribed in Scheme 1–4 to provide compounds of formula (26).

Compounds of formula (34), wherein Y, Y′, Z′, L₂, R₂, R₄, R₅ and R₆ areas defined in formula (I), can be prepared as described in Scheme 7.Indanones of formula (28) can be treated with a base such as, but notlimited to, lithium diisopropylamide and ethyl bromoacetate to provideesters of formula (29). Esters of formula (29) can be treated withborane-tert-butylamine complex and then an aqueous basic solution suchas, but not limited to, sodium hydroxide in water to providehydroxyacids of formula (30). Hydroxyacids of formula (30) can betreated with a strong acid such as, but not limited to, concentratedsulfuric acid with heat in a solvent such as methanol to provide estersof formula (31). Esters of formula (31) can be treated with a reducingagent such as, but not limited to, lithium aluminum hydride to providealcohols of formula (32). Alcohols of formula (32) can be treated withozone followed by dimethylsulfide and ammonium hydroxide to provideisoquinolines of formula (33). Isoquinolines of formula (33) can beprocessed as described in Schemes 1–3 and 5 to provide compounds offormula (34).

Compounds of formula (42), wherein R₂, R₄, R₅ and R₆ are as defined informula (I) and L₂ is —[C(R₁₈)(R₁₉)]_(q)— or a bond can be prepared asdescribed in Scheme 8. 1-(2-Bromoethyl)-4-nitrobenzene can be treatedwith amines of formula (5) to provide amines of formula (37). Amines offormula (37) can be treated with palladium on carbon under a hydrogenatmosphere to provide anilines which can then be treated with a nitrogenprotecting reagent such as, but not limited to, trimethylacetyl chlorideto provide protected anilines of formula (38). Protected anilines offormula (38) can be treated with an organolithium reagent such as, butnot limited to, n-butyllithium, sec-butyllithium, or tert-butyllithiumand N,N-dimethylformamide to provide aldehydes of formula (39). Theaniline of aldehydes of formula (39) can be deprotected using methodswell-known to those skilled in the art such as, but not limited to,heating in aqueous hydrochloric acid to provide aldehydes of formula(40). Aldehydes of formula (40) can be treated with ketones of formula(41) and a base such as, but not limited to, potassium ethoxide toprovide compounds of formula (42).

Compounds of formula (44), wherein R₁, R₄, R₅ and R₆ are as defined informula (I) and L₂ is —[C(R₁₈)(R₁₉)]_(q)— or a bond also can be preparedas described in Scheme 8. Aldehydes of formula (40) can be treated withketones of formula (43) and a base such as, but not limited to,potassium ethoxide to provide compounds of formula (44).

Compounds of formula (41) or (43) can be purchased commercially orsynthesized from procedures which are known to those skilled in the art.One example of such a synthesis as described in Chikashita, H. et al.,Bull. Chem. Soc. Jpn. 61:3637–3648 (1988) involves the deprotonation ofa fused polycyclic compound such as benzothiazole using a base such asn-butyllitium providing an intermediate lithium anion which is reactedwith an electrophile such as N,N-dimethyl acetamide to provide compoundsof formula (41) wherein L₂ is a bond.

Alternatively, a polycyclic compound that is substituted with Cl, Br, Ior triflate can be converted to the corresponding acetate of generalstructure (41) wherein L₂ is a bond, by several methods that are knownto those skilled in the art. In the reaction commonly known asmetal-halide exchange, a polycyclic compound that is substituted with Bror I, can be treated with an alkyl lithium such as n-butyl lithium toprovide an intermediate lithium anion which is with an electrophile suchas N-methoxy-N-methylacetamide. An example of this transformation can befound in Wai, J. S. et. al., J. Med. Chem. (43)26:4923–4926 (2000). Inthe reaction commonly known as the Heck reaction, a polycyclic compoundthat is substituted with Cl, Br, I or triflate, can be reacted with avinyl ether such as N-butyl vinyl ether in the presence of a catalystsuch as palladium acetate to provide acetates of general structure (41),wherein L₂ is a bond. An example of such a transformation can be foundin Viaud, M. et al., Heterocycles, (41)12: 2799–2810 (1995). In thereaction commonly known as the Stille reaction, a polycyclic compoundthat is substituted with Cl, Br, I or triflate, can be coupled with atin-vinyl ether such as 1-ethoxyvinyltri-n-butyltin in the presence of acatalyst such as tetrakis(triphenylphosphine)palladium(0) to provideacetates of general structure (41) wherein L₂ is a bond. An example ofsuch a transformation can be found in Viaud, M. et. al., Tetrahedron53(14): 5159–5168 (1997).

Compounds of formula (41) wherein L₂ is a bond can also be obtained bythe cyclization of a dicarbonyl intermediate with an appropriatereagent. Examples of such cyclization reactions are illustrated in thefollowing references: Badr, M. Z. A. et. al., Bull. Chem. Soc. Jpn.61:1339–1344 (1988); Kaugars, G. et. al., Heterocycles (38)12:2593–2604(1994); Bruni, F. et. al., Heterocycles, 31(6): 1141–1149 (1990); andReddy, K. V. et. al., J. Indian Chem. Soc., 63: 443–445 (1986).

Compounds of formula (50), wherein L₂, R₄, R₅ and R₆ are as defined informula (I), can be prepared as described in Scheme 9. Ethyl7-methoxy-2-methyl-3-quinolinecarboxylate can be prepared using theprocedures described in Synthetic Comm., 17(14): 1647–1653 (1987). Ethyl7-methoxy-2-methyl-3-quinolinecarboxylate can be treated with a reducingagent, such as, but not limited to, lithium aluminum hydride or sodiumborohydride, to provide (7-methoxy-2-methyl-3-quinolinyl)methanol.(7-Methoxy-2-methyl-3-quinolinyl)methanol can be treated with achlorinating reagent, such as, but not limited to, thionyl chloride toprovide 3-(chloromethyl)-7-methoxy-2-methylquinoline.3-(Chloromethyl)-7-methoxy-2-methylquinoline can be treated with sodiumcyanide or potassium cyanide to provide(7-methoxy-2-methyl-3-quinolinyl)acetonitrile.(7-Methoxy-2-methyl-3-quinolinyl)acetonitrile can be treated with acid,such as, but not limited to, glacial acetic acid and concentratedsulfuric acid, in water and 1,4-dioxane with heat to provide(7-methoxy-2-methyl-3-quinolinyl)acetic acid.(7-Methoxy-2-methyl-3-quinolinyl)acetic acid can be treated with areducing agent, such as, but not limited to, B₂H₆, borane-THF complex,or borane-pyridine complex, to provide2-(7-methoxy-2-methyl-3-quinolinyl)ethanol.2-(7-Methoxy-2-methyl-3-quinolinyl)ethanol can be treated withmethanesulfonyl chloride and a base, such as, but not limited to,triethylamine or diisopropylamine to provide2-(7-methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate.2-(7-Methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate can be treatedwith an amine of formula (5) to provide amines of formula (47). Aminesof formula (47) can be treated with BBr₃ to provide hydroxy compounds offormula (48). Hydroxy compounds of formula (48) can be treated withtrifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chlorideto provide triflates of formula (49). Triflates of formula (49) can beprocessed as described in Schemes 1–3 to provide compounds of formula(50).

1,5-Naphthyridines of formula (53), wherein L₂, R₄, R₅ and R₆ are asdefined in formula (I), can be prepared as described in Scheme 10.3,7-Dibromo-[1,5]naphthyridine, prepared as described by W. W. Paudler,J. Org. Chem., 33:1384 (1968), can be treated with(2-ethoxyvinyl)tributylstannane, a halide source, such as, but notlimited to, tetraethylammonium chloride, and a palladium source, suchas, but not limited to, dichlorobis(triphenylphosphine)palladium (II) ina solvent, such as, but not limited to, N,N-dimethylformamide with heat(about 50° C. to about 150° C.) to provide3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine.3-Bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine can be treated with an acid,such as, but not limited to, formic acid at about 0° C. to about 60° C.in a solvent, such as, but not limited to, 1,2-dichloroethane to provide(7-bromo-1,5-naphthyridin-3-yl)acetaldehyde. Alternatively,3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine in a solvent, such as, butnot limited to, tetrahydrofuran can be treated with an aqueous acid,such as, but not limited to, hydrochloric acid at about 0° C. to about60° C. to provide (7-bromo-1,5-naphthyridin-3-yl)acetaldehyde.(7-Bromo-1,5-naphthyridin-3-yl)acetaldehyde can be treated with an amineof formula (5) under reductive amination conditions, such as, but notlimited to, sodium triacetoxyborohydride and an acid, such as, but notlimited to, acetic acid in a solvent, such as, but not limited to,1,2-dichloroethane at about 0° C. to about 50° C. to provide amines offormula (52). Amines of formula (52) can be processed as described inSchemes 1–3 to provide 1,5-naphthyridines of formula (53).

Cinnolines of formula (60), wherein L₂, R₄, R₅ and R₆ are as defined informula (I), can be prepared as described in Scheme 11. Amines offormula (5) can be treated with 3-butynyl methanesulfonate at roomtemperature with stirring for about 1 hour and then heated at about 50°C. for about 24 hours. The mixture is allowed to cool to roomtemperature, and filtered. The filtrate is diluted with acetonitrile toprovide a 0.1 M solution of alkynes of formula (55) for use insubsequent steps. 5-Bromo-2-iodophenylamine, prepared as described bySakamoto in Chem. Pharm. Bull. 35:1823 (1987), can be treated withalkynes of formula (55), a source of palladium (II), such as, but notlimited to, Pd(Ph₃P)₂Cl₂, CuI, and a base, such as, but not limited to,triethylamine in an organic solvent, such as, but not limited to, DMF atabout 50° C. to about 80° C. to provide alkynes of formula (56). Alkynesof formula (56) can be treated with aqueous acid, such as but notlimited to aqueous HCl in the presence of sodium nitrite at about 0° C.to about 100° C. to provide hydroxy cinnolines of formula (57). Hydroxycinnolines of formula (57) can be processed as described in Schemes 1–3to provide hydroxy cinnolines of formula (58). Hydroxy cinnolines offormula (58) can be treated withN-phenylbis(trifluoromethanesulfonimide) and a base, such as, but notlimited to, diisopropylethylamine in an organic solvent, such as, butnot limited to, 1,2-dichloroethane at about 25° C. to about 40° C. toprovide triflates of formula (59). Triflates of formula (59) can betreated with a catalytic palladium source, such as, but not limited to,palladium (II) acetate and a hydrogen donor, such as, but not limitedto, formic acid at about 25° C. to about 50° C. to provide cinnolines offormula (60).

Cinnolines of formula (60), wherein L₂, R₄, R₅ and R₆ are as defined informula (I), also can be prepared as described in Scheme 12.7-Chloro-3-cinnolinol, prepared as described by H. E. Baumgarten, J.Het. Chem., 6:333 (1969), can be treated with trifluoromethanesulfonylchloride or trifluoromethanesulfonic anhydride and a base, such as, butnot limited to, triethylamine or pyridine in a solvent, such as, but notlimited to, dichloromethane at about 0° C. or room temperature toprovide 7-chloro-3-cinnolinyl trifluoromethanesulfonate.7-Chloro-3-cinnolinyl trifluoromethanesulfonate can be treated with(2-ethoxyvinyl)tributylstannane, a halide source, such as, but notlimited to, tetraethylammonium chloride, and a palladium source, suchas, but not limited to, dichlorobis(triphenylphosphine)palladium (II) ina solvent, such as, but not limited to, N,N-dimethylformamide at about50° C. to about 150° C. to provide 7-chloro-3-(2-ethoxyvinyl)cinnoline.7-Chloro-3-(2-ethoxyvinyl)cinnoline can be processed as described inScheme 10 to provide amines of formula (62). Amines of formula (62) canbe processed as described in Schemes 1–3 to provide cinnolines offormula (60).

Cinnolines of formula (67), wherein L₂, R₄, R₅ and R₆ are as defined informula (I), can be prepared as described in Scheme 13.7-Chloro-3-cinnolinyl trifluoromethanesulfonate, prepared as describedin Scheme 12, can be processed as described in Schemes 1–3 to providechlorides of formula (64). Chlorides of formula (64) can be treated with2-(2-ethoxy-vinyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, prepared asdescribed by C. M. Vogels in Chem. Commun. 1: 51 (2000) a palladiumsource, such as, but not limited to,tris(dibenzylideneacetone)dipalladium (0), tri(tert-butyl)phosphine ordichloro(di-tert-butylphosphinous acid)palladium (II) dimer and a basesuch as cesium fluoride, in a solvent, such as, but not limited to,1,4-dioxane at about 30° C. to about 120° C. to provide ethers offormula (65). Ethers of formula (65) can be processed as described inScheme 10 to provide cinnolines of formula (67).

Quinolines of formula (73), wherein L₂, R₄, R₅ and R₆ are as defined informula (I), can be prepared as described in Scheme 14.2-(3-Nitrophenyl)ethanol, CAS #100-27-6, can be treated withmethanesulfonyl chloride (or toluenesulfonyl chloride), and a base, suchas, but not limited to, triethylamine in a solvent, such as, but notlimited to, methylene chloride to provide 2-(3-nitrophenyl)ethylmethanesulfonate. 2-(3-Nitrophenyl)ethyl methanesulfonate can be treatedwith amines of formula (5) and a base, such as, but not limited to,potassium carbonate in a solvent, such as, but not limited to,acetonitrile to provide amines of formula (70). Amines of formula (70)can be treated with hydrogen with a palladium source, such as but notlimited to palladium on carbon in a solvent, such as, but not limitedto, methanol, ethanol, or ethyl acetate to provide anilines of formula(71). Anilines of formula (71) can be treated with2,2,3-tribromopropanal as described in S. W. Tinsley, J. Amer. Chem.Soc. 77:4175–4176 (1955), to provide quinolines of formula (72).Quinolines of formula (72) can be processed as described in Schemes 1–3to provide quinolines of formula (73).

Naphthyridines of formula (80), wherein L₂, R₄, R₅ and R₆ are as definedin formula (I), can be prepared as described in Scheme 15.5-Bromo-2-iodopyridine (CAS# 223463-13-6) can be processed as describedin Schemes 1–3 to provide pyridines of formula (76). Compounds offormula (76) can be treated with a base, such as, but not limited to,lithium diisopropylamide and N,N-dimethylformamide, as described inNumata et al., Synthesis, 306–311 (1999), to provide compounds offormula (77). Compounds of formula (77) can be treated with3-butyn-1-ol, CuI, a base such as, but not limited to, triethylamine,and palladium source, such as, but not limited to, Pd(PPh₃)₂Cl₂ in asolvent, such as but not limited to N,N-dimethylformamide to providealkynes of formula (78). Alkynes of formula (78) can be treated withammonia at about 80° C. in a solvent, such as, but not limited to,ethanol to provide naphthyridines of formula (79). Naphthyridines offormula (79) can be processed as described in Scheme 1 to providenaphthyridines of formula (80).

Naphthyridines of formula (86), wherein L₂, R₄, R₅ and R₆ are as definedin formula (I), can be prepared as described in Scheme 16.6-Bromo-2-pyridinecarbaldehyde can be treated with N-iodosuccinimide insulfuric acid and acetic acid to provide6-bromo-3-iodo-2-pyridinecarbaldehyde and6-bromo-5-iodo-2-pyridinecarbaldehyde.6-Bromo-3-iodo-2-pyridinecarbaldehyde can be treated withtert-butylamine in a solvent, such as, but not limited to, THF toprovide imine (84). Imine (84) can be treated with 3-butyn-1-ol, CuI, abase, such as, but not limited to, triethylamine or diisopropylamine,and a palladium source, such as, but not limited to, Pd(PPh₃)₂Cl₂ in asolvent, such as but not limited to N,N-dimethylformamide to providealcohols of formula (85). Alcohols of formula (85) can be processed asdescribed in Schemes 1–3 to provide naphthyridines of formula (86).

Naphthyridines of formula (91), wherein R₄, R₅ and R₆ are as defined informula (I), can be prepared as described in Scheme 17. Imines offormula (84), prepared as described in Scheme 16, can be treated withalkynes of formula (88), CuI, a base, such as, but not limited to,triethylamine or diisopropylamine, and a palladium source, such as, butnot limited to, Pd(PPh₃)₂Cl₂ in a solvent, such as but not limited toN,N-dimethylformamide to provide naphthyridines of formula (89).Naphthyridines of formula (89) can be treated with an alkyllithiumreagent, such as, but not limited to, methyllithium, n-butyllithium,sec-butyllithium, or t-butyllithium, and ethylene oxide in a solvent,such as, but not limited to, THF or diethyl ether to provide alcohols offormula (90). Alcohols of formula (90) can be treated as described inSchemes 1–3 to provide naphthyridines of formula (91).

Isoquinolines of formula (95), wherein R₄, R₅ and R₆ are as defined informula (I), can be prepared as described in Scheme 18. Methyl2-iodobenzoate can be treated with N-bromosuccinimide in acetic acid andsufuric acid to provide methyl 5-bromo-2-iodobenzoate. Methyl5-bromo-2-iodobenzoate can be treated with a reducing agent, such as,but not limited to, sodium borohydride or lithium aluminum hydride in asolvent, such as, but not limited to, THF, ethanol, or a mixturethereof, to provide (5-bromo-2-iodophenyl)methanol.(5-Bromo-2-iodophenyl)methanol can be treated with an oxidizing agent,such as, but not limited to, pyridinium chlorochromate, pyridiniumdichromate, MnO₂, a peracid such as meta-chloroperoxybenzoic acid, orSwern conditions (DMSO/Cl(CO)₂Cl/TEA) to provide5-bromo-2-iodobenzaldehyde. 5-Bromo-2-iodobenzaldehyde can be treatedwith tert-butylamine in a solvent, such as, but not limited to, THF toprovide N-[(5-bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine.N-[(5-Bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine can be treatedwith alkynes of formula (88), CuI, a base, such as, but not limited to,triethylamine or diisopropylamine, and a palladium source, such as, butnot limited to, Pd(PPh₃)₂Cl₂ in a solvent, such as but not limited toN,N-dimethylformamide to provide isoquinolines of formula (93).Isoquinolines of formula (93) can be treated with an alkyllithiumreagent, such as, but not limited to, methyllithium, n-butyllithium,sec-butyllithium, or t-butyllithium, and ethylene oxide in a solvent,such as, but not limited to, THF or diethyl ether to provide alcohols offormula (94). Alcohols of formula (94) can be treated as described inSchemes 1–3 to provide isoquinolines of formula (95).

Isoquinolines of formula (34a) are a subgenus of compounds (34), whereinX, Y′, and Z′ are all carbon atoms, for instance CH, and L₂, R₄, R₅ andR₆ are as defined in formula (I), and the compounds of the subgenus(34a) can be prepared as described in Scheme 19. Methyl 2-iodobenzoatecan be treated with N-bromosuccinimide in acetic acid and sufuric acidto provde methyl 5-bromo-2-iodobenzoate. Methyl 5-bromo-2-iodobenzoatecan be treated with a reducing agent, such as, but not limited to,sodium borohydride or lithium aluminum hydride in a solvent, such as,but not limited to, THF, ethanol, or a mixture thereof, to provide(5-bromo-2-iodophenyl)methanol. (5-Bromo-2-iodophenyl)methanol can betreated with an oxidizing agent, such as, but not limited to, pyridiniumchlorochromate, pyridinium dichromate, MnO₂, a peracid such asmeta-chloroperoxybenzoic acid, or Swern conditions (DMSO/Cl(CO)₂Cl/TEA)to provide 5-bromo-2-iodobenzaldehyde. 5-Bromo-2-iodobenzaldehyde can betreated with tert-butylamine in a solvent, such as, but not limited to,THF to provide N-[(5-bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine.N-[(5-Bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine can be treatedwith the alkyne but-3-yn-1-ol, CuI, a base, such as, but not limited to,triethylamine or diisopropylamine, and a palladium source, such as, butnot limited to, Pd(PPh₃)₂Cl₂ in a solvent, such as, but not limited to,N,N-dimethylformamide to provide an isoquinoline. The2-hydroxyethylisoquinoline can be treated as described in Schemes 1–3,and 5 to provide isoquinolines of formula (34a).

Quinoxalines of formula (105), wherein L₂, R₆, R₄ and R₅ are as definedfor formula (I), can be prepared as described in Scheme 20. Amines offormula (37), prepared as described in Scheme 8, can be treated withpalladium on carbon under a hydrogen atmosphere to provide anilines thatcan then be treated with acetic anhydride in a solvent such as a mixtureof sulfuric acid and water to provide acetamides of formula (100).Acetamides of formula (100) can be nitrated using conditions well knownto those skilled in the art. One example of such a nitration reactionutilizes nitric acid in sulfuric acid in the presence of aceticanhydride to provide acetamides of formula (101). Acetamides of formula(101) can be converted to Boc protected nitroanilines using a proceduredescribed in Grehen, L, et. al, Acta Chem. Scand. Ser B. 41(1):18–23, inwhich the acetamide is reacted with di-tert-butyldicarbonate in thepresence of 4-dimethylaminopyridine followed by treatment with2-diethylaminodiethylamine to provide a Boc-protected nitroaniline whichcan be treated with palladium on carbon under a hydrogen atmosphere toprovide anilines of formula (102). Anilines of formula (102) can bereacted with a bromoacetate to provide anilines of formula (110) whereinR₉₅ is alkyl. Anilines of formula (110) can be treated with an acid suchas, but not limited to, trifluoroacetic acid with heating to providedihydroquinoxalinones of formula (111). Dihydroquinoxalinones of formula(111) can be oxidized using an oxidizing agent such as, but not limitedto, silver nitrate to provide quinoxalinones of formula (112).Quinoxalinones of formula (112) can be treated with triflouroaceticanhydride in the presence of a base such as 2,6-lutidine in a solventsuch as dichloromethane to provide compounds of structure (113) whereinW is triflate. Alternatively, quinoxalinones of formula (112) can betreated with POCl₃ to provide compounds of structure (113) wherein W isCl. Compounds of formula (113) can be processed as described in Schemes1–3 to provide quinoxalines of formula (105).

Quinoxalines of formula (105), wherein L₂, R₆, R₄ and R₅ are as definedin formula (I), can be prepared as described in Scheme 21.2-Chloro-quinoxaline-6-carboxylic acid (Wolf et al., J. Amer. Chem. Soc.71: 6–10 (1949)) can be reduced to (2-chloro-quinoxalin-6-yl)-methanolusing a reducing agent such as, but not limited to, borane-THF complex.(2-Chloro-quinoxalin-6-yl)-methanol can be processed as described inScheme 5 to provide quinoxalines of formula (105).

Quinazolines of formula (123), wherein R₄, R₅ and R₆ are as defined informula (I), can be prepared as described in Scheme 22. Anilines offormula (40) prepared as described in Scheme 8, can be treated with acidchlorides of formula (121) in the presence of a base such as pyridine ina solvent such as dichloromethane to provide amides of formula (122).Amides of formula (122) can be treated with a source of ammonia, such asaqueous ammonium hydroxide, and heated to provide quinazolines offormula (123).

Quinazolines of formula (123), wherein L₂, R₄, R₅ and R₆ are as definedin formula (I) is aryl or heteroaryl can also be prepared as describedin Scheme 23. Anilines of formula (40), prepared as described in Scheme8, can be treated with urea and heated as described in Troeger, et. al.,.Prakt. Chem. 117:181 (1927), to provide quinazolinones of formula(130). Quinazolinones of formula (130) can be treated with triflicanhydride in the presence of a base such as 2,6-lutidine in a solventsuch as dichloromethane to provide triflates of general structure (131).Triflates of formula (131) can be treated as described in Schemes 1–3 toprovide quinoxalines of formula (123).

Compounds of formula (144) and (145), wherein Y, Y′, Z′, L₂, R₂, R₄, R₅and R₆ are as defined in formula (I), can be prepared as described inScheme 24. Nitrobenzenes of formula (138) can be treated with a reducingagent such as, but not limited to, platinum on carbon under a hydrogenatmosphere to provide diaminobenzenes of formula (139). Diaminobenzenesof formula (139) can be treated with 2-oxopropanal to provide a mixtureof bromides of formula (140) and (141). Bromides of formula (140) and(141) can be treated with formaldehyde and amines of formula (5) toprovide a mixture of aminobromides of formula (142) and (143).Aminobromides of formula (142) and (143) can be processed as describedin Schemes 1–3 to provide compounds of formula (144) and (145).

Compounds of formula (154), wherein Y, Y′, Z′, L₂, R₂, R₄, R₅ and R₆ areas defined in formula (I), can be prepared as described in Scheme 25.Compounds of formula (138), purchased or prepared using known methods inthe art, can be treated with NaNO₂ and acid, such as, but not limitedto, concentrated sulfuric acid followed by treatment with Kl to provideiodo compounds of formula (148). Iodo compounds of formula (148) can betreated with SnCl₂ and an acid such as, but not limited, concentratedHCl to provide compounds of formula (149). Compounds of formula (149)can be treated with but-3-yn-1-ol, copper (I) iodide, base such as, butnot limited to triethylamine, and a metal catalyst such as but notlimited to PdCl₂(PPh₃)₂ to provide alkynes of formula (150). Alkynes offormula (150) can be treated with NaNO₂ and an acid such as, but notlimited to, 6M HCl to provide compounds of formula (151). Compounds offormula (151) can be treated with POCl₃ to provide chlorides of formula(152). Chlorides of formula (152) can be treated as described in Schemes1–3 to provide compounds of formula (153). Compounds of formula (153)can be treated with amines of formula (5) to provide compounds offormula (154).

Compounds of formula (159–161), wherein Y, Y′, Z′, L₂, R₂, R₄, R₅ and R₆are as defined in formula (I), can be prepared as described in Scheme26. Compounds of formula (149), can be treated with amines of formula(55), copper (I) iodide, a base such as, but not limited totriethylamine, and a metal catalyst such as, but not limited to,PdCl₂(PPh₃)₂ to provide alkynes of formula (157). Alkynes of formula(157) can be treated with NaNO₂ and an acid such as, but not limited to,6 M HCl to provide compounds of formula (158). Compounds of formula(158) can be converted to compounds of formula (159) using reactionconditions as described in Schemes 1–3 to provide compounds of formula(159). Compounds of formula (159) can be treated with an alkyl halidesuch as, but not limited to, iodomethane or iodoethane and a base suchas, but not limited to, triethylamine or sodium hydride to providecompounds of formula (160). Compounds of formula (159) can be treatedwith phosphorus oxychloride to provide chlorides of formula (161).Phosphorous oxybromide may also be used to generate the correspondingbromides.

An alternative method for preparing compounds of formula (160–161) andmethods for preparation of compounds of formula (167–169), wherein Y,Y′, Z′, L₂, R₂, R₄, R₅ and R₆ are as defined in formula (I) is describedin Scheme 27. Compounds of general formula (151), can be treated with areagent for protecting a hydroxy group known to those of skill in theart such as, but not limited to, tert-butyldimethylsilyl chloride orbenzyl bromide, and a base such as, but not limited to, sodiumbicarbonate or imidazole to provide compounds of formula (163) whereinPG is the hydroxy protecting group. Compounds of formula (163) can betreated with methanesulfonyl chloride (or toluenesulfonyl chloride) anda base such as, but not limited to, diisopropylamine or triethylamine toprovide sulfonates of formula (164). Sulfonates of formula (164) can betreated with amines of formula (5) to provide compounds of formula(165). Compounds of formula (165) can be treated as described in Schemes1–3 to provide compounds of formula (166). The hydroxy protecting groupof compounds of formula (166) can be removed using methods known tothose in the art such as, but not limited to, treatment with fluorideion, acid, or hydrogenation in the presence of a metal catalyst (H₂ andPd/C) followed by treatment with phosphorus oxychloride to providechlorides of formula (161). Phosphorous oxybromide may also be used togenerate the corresponding bromides. Chlorides of formula (161) can betreated with nucleophiles such as, but not limited to, alkoxides, alkylmercaptans, alkyl Grignards, or sodium cyanide to provide compounds offormula (160, 167–169).

The compounds and intermediates of the invention may be isolated andpurified by methods well-known to those skilled in the art of organicsynthesis. Examples of conventional methods for isolating and purifyingcompounds can include, but are not limited to, chromatography on solidsupports such as silica gel, alumina, or silica derivatized withalkylsilane groups, by recrystallization at high or low temperature withan optional pretreatment with activated carbon, thin-layerchromatography, distillation at various pressures, sublimation undervacuum, and trituration, as described for instance in “Vogel's Textbookof Practical Organic Chemistry”, 5th edition (1989), by Furniss,Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical,Essex CM20 2JE, England.

The compounds of the invention have at least one basic nitrogen wherebythe compound can be treated with an acid to form a desired salt. Forexample, a compound may be reacted with an acid at or above roomtemperature to provide the desired salt, which is deposited, andcollected by filtration after cooling. Examples of acids suitable forthe reaction include, but are not limited to tartaric acid, lactic acid,succinic acid, as well as mandelic, atrolactic, methanesulfonic,ethanesulfonic, toluenesulfonic, naphthalenesulfonic, carbonic, fumaric,gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic,phosphoric, sulfuric, citric, or hydroxybutyric acid, camphorsulfonic,malic, phenylacetic, aspartic, glutamic, and the like.

Compositions of the Invention

The invention also provides pharmaceutical compositions comprising atherapeutically effective amount of a compound of formula (I) incombination with a pharmaceutically acceptable carrier. The compositionscomprise compounds of the invention formulated together with one or morenon-toxic pharmaceutically acceptable carriers. The pharmaceuticalcompositions can be formulated for oral administration in solid orliquid form, for parenteral injection or for rectal administration.

The term “pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like, and suitable mixturesthereof), vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate, or suitable mixtures thereof. Suitablefluidity of the composition may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms may be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Suspensions, in addition to the active compounds, may contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of theinvention can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the invention is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of materials which can be useful for delaying releaseof the active agent can include polymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. A desired compound ofthe invention is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, ear drops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the invention may also be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the invention, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., (1976), p 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants, which canbe required. Opthalmic formulations, eye ointments, powders andsolutions are contemplated as being within the scope of this invention.Aqueous liquid compositions comprising compounds of the invention alsoare contemplated.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts, esters, or amides derived frominorganic or organic acids. The term “pharmaceutically acceptable salts,esters and amides,” as used herein, refer to carboxylate salts, aminoacid addition salts, zwitterions, esters and amides of compounds offormula (I) which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like, arecommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid.

Representative acid addition salts include, but are not limited toacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate. Preferred salts of thecompounds of the invention are the tartrate and hydrochloride salts.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids which can be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acidand such organic acids as oxalic acid, maleic acid, succinic acid, andcitric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium, and aluminum salts, and the like,and nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine and the such as.Other representative organic amines useful for the formation of baseaddition salts include ethylenediamine, ethanolamine, diethanolamine,piperidine, and piperazine.

The term “pharmaceutically acceptable ester,” as used herein, refers toesters of compounds of the invention which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Examples of pharmaceutically acceptable,non-toxic esters of the invention include C₁-to-C₆ alkyl esters andC₅-to-C₇ cycloalkyl esters, although C₁-to-C₄ alkyl esters arepreferred. Esters of the compounds of formula (I) may be preparedaccording to conventional methods. For example, such esters may beappended onto hydroxy groups by reaction of the compound that containsthe hydroxy group with acid and an alkylcarboxylic acid such as aceticacid, or with acid and an arylcarboxylic acid such as benzoic acid. Inthe case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine and an alkyl halide, alkyl trifilate, forexample with methyliodide, benzyl iodide, cyclopentyl iodide. They alsomay be prepared by reaction of the compound with an acid such ashydrochloric acid and an alkylcarboxylic acid such as acetic acid, orwith acid and an arylcarboxylic acid such as benzoic acid.

The term “pharmaceutically acceptable amide,” as used herein, refers tonon-toxic amides of the invention derived from ammonia, primary C₁-to-C₆alkyl amines and secondary C₁-to-C₆ dialkyl amines. In the case ofsecondary amines, the amine may also be in the form of a 5- or6-membered heterocycle containing one nitrogen atom. Amides derived fromammonia, C₁-to-C₃ alkyl primary amides and C₁-to-C₂ dialkyl secondaryamides are preferred. Amides of the compounds of formula (I) may beprepared according to conventional methods. Pharmaceutically acceptableamides are prepared from compounds containing primary or secondary aminegroups by reaction of the compound that contains the amino group with analkyl anhydride, aryl anhydride, acyl halide, or aryl halide. In thecase of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine,for example with methylamine, diethylamine, piperidine. They also may beprepared by reaction of the compound with an acid such as sulfuric acidand an alkylcarboxylic acid such as acetic acid, or with acid and anarylcarboxylic acid such as benzoic acid under dehydrating conditions aswith molecular sieves added. The composition can contain a compound ofthe invention in the form of a pharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Prodrugs of the invention may be rapidly transformed in vivo to a parentcompound of formula (I), for example, by hydrolysis in blood. A thoroughdiscussion is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987), herebyincorporated by reference.

The invention contemplates pharmaceutically active compounds eitherchemically synthesized or formed by in vivo biotransformation tocompounds of formula (I).

Methods of the Invention

Compounds and compositions of the invention are useful for modulatingthe effects of histamine-3 receptors. In particular, the compounds andcompositions of the invention can be used for treating and preventingdisorders modulated by the histamine-3 receptors. Typically, suchdisorders can be ameliorated by selectively modulating the histamine-3receptors in a mammal, preferably by administering a compound orcomposition of the invention, either alone or in combination withanother active agent as part of a therapeutic regimen.

The compounds of the invention, including but not limited to thosespecified in the examples, possess an affinity for the histamine-3receptors. As histamine-3 receptor ligands, the compounds of theinvention may be useful for the treatment and prevention of diseases orconditions such as acute myocardial infarction, Alzheimer's disease,asthma, attention-deficit hyperactivity disorder, bipolar disorder,cognitive dysfunction, cognitive deficits in psychiatric disorders,deficits of memory, deficits of learning, dementia, cutaneous carcinoma,drug abuse, diabetes, type II diabetes, depression, epilepsy,gastrointestinal disorders, inflammation, insulin resistance syndrome,jet lag, medullary thyroid carcinoma, melanoma, Meniere's disease,metabolic syndrome, mild cognitive impairment, migraine, mood andattention alteration, motion sickness, narcolepsy, neurogenicinflammation, obesity, obsessive compulsive disorder, pain, Parkinson'sdisease, polycystic ovary syndrome, schizophrenia, cognitive deficits ofschizophrenia, seizures, septic shock, Syndrome X, Tourette's syndrome,vertigo, and sleep disorders.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat septic shock andcardiovascular disorders, in particular, acute myocardial infarction maybe demonstrated by Imamura et al., Circ. Res., 78:475–481 (1996);Imamura et. al., Circ. Res., 78:863–869 (1996); R. Levi and N. C. E.Smith, “Histamine H₃-receptors: A new frontier in myocardial ischemia”,J. Pharm. Exp. Ther., 292:825–830 (2000); and Hatta, E., K. Yasuda andR. Levi, “Activation of histamine H₃ receptors inhibits carrier-mediatednorepinephrine release in a human model of protracted myocradialischemia”, J. Pharm. Exp. Ther., 283:494–500 (1997).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat sleep disorders,in particular, narcolepsy may be demonstrated by Lin et al., Brain Res.,523:325–330 (1990); Monti, et al., Neuropsychopharmacology 15:31–35(1996); Sakai, et al., Life Sci., 48:2397–2404 (1991);Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol., 67:75–78(1989); P. Panula, et al., Neuroscience 44:465–481 (1998); Wada, et al.,Trends in Neuroscience 14:415 (1991); and Monti, et al., Eur. J.Pharmacol. 205:283 (1991).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat cognition andmemory process disorders may be demonstrated by Mazurkiewicz-Kwileckiand Nsonwah, Can. J. Physiol. Pharmacol., 67:75–78 (1989); P. Panula, etal., Neuroscience, 82:993–997 (1997); Haas, et al., Behav. Brain Res.,66:41–44 (1995); De Almeida and Izquierdo, Arch. Int. Pharmacodyn.,283:193–198 (1986); Kamei et al., Psychopharmacology, 102:312–318(1990); Kamei and Sakata, Jpn. J. Pharmacol., 57:437–482 (1991);Schwartz et al., Psychopharmacology, The fourth Generation of Progress.Bloom and Kupfer (eds). Raven Press, New York, (1995) 397; and Wada, etal., Trends in Neurosci., 14:415 (1991).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat attention-deficithyperactivity disorder (ADHD) may be demonstrated by Shaywitz et al.,Psychopharmacology, 82:73–77 (1984); Dumery and Blozovski, Exp. BrainRes., 67:61–69 (1987); Tedford et al., J. Pharmacol. Exp. Ther.,275:598–604 (1995); Tedford et al., Soc. Neurosci. Abstr., 22:22 (1996);and Fox, et al., Behav. Brain Res., 131:151–161 (2002).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat seizures, inparticular, epilepsy may be demonstrated by Yokoyama, et al., Eur. J.Pharmacol., 234:129 (1993); Yokoyama and linuma, CNS Drugs 5:321 (1996);Onodera et al., Prog. Neurobiol., 42:685 (1994); R. Leurs, R. C.Vollinga and H. Timmerman, “The medicinal chemistry and therapeuticpotential of ligands of the histamine H₃ receptor”, Progress in DrugResearch 45:170–165, (1995); Leurs and Timmerman, Prog. Drug Res.,39:127 (1992); The Histamine H₃ Receptor, Leurs and Timmerman (eds),Elsevier Science, Amsterdam, The Netherlands (1998); and H. Yokoyama andK. Iinuma, “Histamine and Seizures: Implications for the treatment ofepilepsy”, CNS Drugs, 5(5):321–330 (1995).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat motion sickness,Alzheimer's disease, and Parkinson's disease may be demonstrated byOnodera, et al., Prog. Neurobiol., 42:685 (1994); Leurs and Timmerman,Prog. Drug Res., 39:127 (1992); and The Histamine H₃ Receptor, Leurs andTimmerman (eds), Elsevier Science, Amsterdam, The Netherlands (1998).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat narcolepsy,schizophrenia, depression, and dementia may be demonstrated by R. Leurs,R. C. Vollinga and H. Timmerman, “The medicinal chemistry andtherapeutic potential of ligands of the histamine H₃ receptor”, Progressin Drug Research 45:170–165 (1995); The Histamine H₃ Receptor, Leurs andTimmerman (eds), Elsevier Science, Amsterdam, The Netherlands (1998);and Perez-Garcia C, et. al., and Psychopharmacology (Berl) 142(2):215–20(February, 1999).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat sleep disorders,cognitive dysfunction, mood and attention alteration, vertigo and motionsickness, and treatment of cognitive deficits in psychiatric disordersmay be demonstrated by Schwartz, Physiol. Review 71:1–51 (1991).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat mild cognitiveimpairment, deficits of memory, deficits of learning and dementia may bedemonstrated by C. E. Tedford, in “The Histamine H₃ Receptor: a targetfor new drugs”, the Pharmacochemistry Library, vol. 30 (1998) edited byR. Leurs and H. Timmerman, Elsevier (New York). p. 269 and referencesalso contained therein.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat obesity may bedemonstrated by Leurs, et al., Trends in Pharm. Sci., 19:177–183 (1998);E. Itoh, M. Fujimiay, and A. Inui, “Thioperamide, A histamine H₃receptor antagonist, powerfully suppresses peptide YY-induced foodintake in rats,” Biol. Psych., 45(4):475–481 (1999); S. I. Yates, etal., “Effects of a novel histamine H₃ receptor antagonist, GT-2394, onfood intake and weight gain in Sprague-Dawley rats,” Abstracts, Societyfor Neuroscience, 102.10:219 (November, 2000); and C. Bjenning, et al.,“Peripherally administered ciproxifan elevates hypothalamic histaminelevels and potently reduces food intake in the Sprague Dawley rat,”Abstracts, International Sendai Histamine Symposium, Sendai, Japan, #P39(November, 2000).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat inflammation andpain may be demonstrated by Phillips, et al., Annual Reports inMedicinal Chemistry 33:31–40 (1998).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat migraine may bedemonstrated by R. Leurs, R. C. Vollinga and H. Timmerman, “Themedicinal chemistry and therapeutic potential of ligands of thehistamine H₃ receptor,” Progress in Drug Research 45:170–165 (1995);Matsubara, et al., Eur. J. Pharmacol., 224:145 (1992); and Rouleau, etal., J. Pharmacol. Exp. Ther., 281:1085 (1997).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat cancer, inparticular, melanoma, cutaneous carcinoma and medullary thyroidcarcinoma may be demonstrated by Adam Szelag, “Role of histamineH₃-receptors in the proliferation of neoplastic cells in vitro,” Med.Sci. Monit., 4(5):747–755 (1998); and C. H. Fitzsimons, et al.,“Histamine receptors signalling in epidermal tumor cell lines with H-rasgene alterations,” Inflammation Res., 47 (Suppl 1):S50–S51 (1998).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat vestibulardysfunctions, in particular, Meniere's disease may be demonstrated by R.Leurs, R. C. Vollinga and H. Timmerman, “The medicinal chemistry andtherapeutic potential of ligands of the histamine H₃ receptor,” Progressin Drug Research 45:170–165 (1995), and Pan, et al., Methods andFindings in Experimental and Chemical Pharmacology 21:771–777 (1998).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat asthma may bedemonstrated by A. Delaunois A., et al., “Modulation of acetylcholine,capsaicin and substance P effects by histamine H₃ receptors in isolatedperfused rabbit lungs,” European Journal of Pharmacology277(2–3):243–250 (1995); and Dimitriadou, et al., “Functionalrelationship between mast cells and C-sensitive nerve fibres evidencedby histamine H₃-receptor modulation in rat lung and spleen,” ClinicalScience 87(2):151–163 (1994).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat allergic rhinitismay be demonstrated by McLeod, et al., Progress in Resp. Research 31:133(2001).

Compounds of the invention are particularly useful for treating andpreventing a condition or disorder affecting the memory or cognition,for example Alzheimer's disease, attention-deficit hyperactivitydisorder, schizophrenia, or the cognitive deficits of schizophrenia.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the invention can be employed in pureform or, where such forms exist, in pharmaceutically acceptable salt,ester, amide or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptablecarriers. The phrase “therapeutically effective amount” of the compoundof the invention means a sufficient amount of the compound to treatdisorders, at a reasonable benefit/risk ratio applicable to any medicaltreatment. It will be understood, however, that the total daily usage ofthe compounds and compositions of the invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.0003 to about 30mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.01 to about 0.1 mg/kg/day. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration; consequently, single dose compositions maycontain such amounts or submultiples thereof to make up the daily dose.

The compounds and processes of the invention will be better understoodby reference to the following examples, which are intended as anillustration of and not a limitation upon the scope of the invention.

REFERENCE EXAMPLES Reference Example 1 Preparation of(2R)-2-methylpyrrolidine and (2S)-2-methylpyrrolidine

(2R)-2-Methylpyrrolidine tartrate was prepared via resolution of2-methylpyrrolidine with D-tartaric acid using procedures described byWilliam Gaffield, et al. in Tetrahedron, 37:1861–1869 (1981) or,alternatively, prepared from L-prolinol by methods described by Karrerand Ehrhardt in Helv. Chim. Acta, 34: 2202, 2208 (1951).(2R)-2-methylpyrrolidine hydrobromide also is a suitable source of(2R)-2-methylpyrrolidine, and was prepared using the procedure describedby Nijhuis, Walter H. N., et al., J. Org. Chem., 54(1): 209–216, 214(1989). Other procedures describing the synthesis of(2R)-2-methylpyrrolidine and salts thereof can be found in Andres, JoseM., et al. Eur. J. Org. Chem., 9:1719–1726 (2000); and Elworthy, ToddR.; Meyers, A. I., Tetrahedron, 50(20): 6089–6096 (1994).

(2S)-2-Methylpyrrolidine can be substituted for (2R)-2-methylpyrrolidinein the experimental procedures provided herein. The(2S)-2-methylpyrrolidine can be prepared by procedures described in Kim,Mahn-Joo, et al., Bioorg. Med. Chem. Lett. 6(1):71–76 (1996).

Reference Example 2 Preparation of Boronic Acid and Ester Reagents

There are many bicyclic and tricyclic boronic acids and boronic acidesters that are available commercially or that can be prepared asdescribed in the scientific literature of synthetic organic chemistry.Non-exhaustive examples of boronic acid and boronic acid ester reagentsfor the synthesis of compounds of formula (I) are provided in Table 1,below, and the following description.

TABLE 1 Examples of Boronic Acid and Boronic Acid Ester ReagentsCommercial Source, Chemical Abstracts Boronic Acid or Boronic Acid EsterNumber or Literature Reference Thianthrene-1-boronic acid AldrichChemical Company, Inc. Benzoxazole-5-boronic acid Cat # 110831, AsymchemLaboratories, Inc. Benzothiazole-5-boronic acid Cat # 1464, DigitalSpecialty Chemicals, Inc. 4-Methyl-7-(4,4,5,5-tetramethyl-1,3,2- Cat #CC13539CB, dioxaborolan-2-yl)-3,4-dihydro-2h-1,4- Acros Organics USAbenzoxazine 10-Methyl-3-(4,4,5,5-tetramethyl- Kraemer, C. S.; et. al.[1,3,2]dioxaborolan-2-yl)-10H- Synthesis 2002, 9, 1163–1170.phenothiazine (1,4-Dihydro-4,4-dimethyl-2-oxo-2H- Zhang, P.; et. al. J.Med. 3,1-benzoxazin-6-yl)boronic acid Chem. 2002, 45, 4379–4382.

Boronic acid esters of formula (14),(R₉₄O)₂B-L₂R₆  (14),wherein L₂ is a bond, and wherein R₉₄ is lower alkyl or wherein R₉₄ canbe taken together to form a ring which may itself be substituted withalkyl or aryl groups, may serve as synthetic replacements for boronicacids of formula (14), wherein R₉₄ is hydrogen. Boronic acids of formula(14) and boronic acid esters of formula (14) are commercially availableor can be prepared by methods well known to those skilled in the art ofsynthetic organic chemistry. For instance, Takagi et al. (TetrahedronLetters, 43:5649–5651 (2002)) prepared heteroaryl pinacolborane estersof using heteroaromatic compounds and reaction with bis(pinacolborane)in the presence of an iridium catalysis ofIrCl[COD]2-(4,4′-di-t-butyl-2,2′-bipyridine in octane. Other methodshave been described wherein aryl halides and heteroaryl halides aretransmetallated with alkyl lithiums or Grignard reagents, then treatedwith trialkylborate esters, then treated with acid to produce boronicacids and boronic acid esters (B. T. O'Neill, et al., Organic Letters,2:4201 (2000); M. D. Sindkhedkar, et al., Tetrahedron, 57:2991 (2001);W. C. Black, et al., Journal of Medicinal Chemistry, 42:1274 (1999);Letsinger; Dandegaonker, J. Amer. Chem. Soc., 81:498–501 (1959);Carroll, F. Ivy, et al. J. Med. Chem., 2229–2237 (2001). Another methodis the Miyaura reaction described in Ishiyama, Tatsuo; Ishida, Kousaku,Miyaura, Norio, Tetrahedron, 9813–9816 (2001) in which aryl andheteroaryl halides are reacted with bis(pinacolborane), KOAc, andPd₂dba₃ and tris-cyclohexylphosphine or PdCl₂dppf (Ishiyama, et al.Tetrahedron, 9813–9816 (2001)). Another method for preparation ofboronic acids and boronic acid esters is the reaction described in O.Baudoin, et al., J. Org. Chem., 65:9268–9271 (2000), in which aryl andheteroaryl halides or triflates are reacted with a dialkoxyborane suchas pinacolborane, in the presence of Et₃N and Pd(OAc)₂ in dioxane.Methodologies for preparing compounds of formula (14) wherein one of therings of R₆ is a cycloalkyl ring can be prepared, for example, frombicyclic or polycyclic compounds wherein one of the rings is acycloalkene (for example, see H. C. Brown, et al., J. Amer. Chem. Soc.,95:2396–2397 (1973) and H. C. Brown, et al., J. Amer. Chem. Soc.,98:1798–1806 (1976)) or cycloalkyl Grignard or cycloalkyl lithiumintermediates (see, for example, Graf et al., Tetrahedron, 55:8801–8814(1999) and Michailow, et al., Izv. Akad. Nauk SSSR Ser. Khim, 76:78(1959)).

Reference Example 3 Preparation of Stannane-Type Reagents

Reagents such Bu₃SnR₆ are suitable for reactions under Stille conditionsin Scheme 1 and are commercially available. However, where the reagentssuch as Me₃SnR₆, Bu₃SnR₆, and R₆ZnCl wherein R₆ is bicyclic or tricyclicare not commercially available, they may be prepared by methodsavailable to one with skill in the art. Examples of such methods includelithium halogen-metal exchange of heteroaryl, heterocyclic or arylhalides, followed by treatment with Me₃SnCl (Li, et al. J. Med. Chem.1996, 39, 1846), Bu₃SnCl, ZnCl₂, or B(OCH₃)₃ (O'Neill, et al. Org. Lett.2000, 2, 4201; Sindkhedkar, et al. Tet. 2001, 57, 2991) and magnesiumhalogen-metal exchange with isopropylmagnesium chloride as described inKnochel, et al. J. Org. Chem. 2000, 65, 4618–4634, followed by treatmentwith Me₃SnCl, Bu₃SnCl, or ZnCl₂. Heteroaryl halides and triflates can betreated with trimethylstannyl sodium as described in A. O. Koren, et al.J. Med. Chem. 1998, 41, 3690, to give Me₃SnR₆. Heteroaryl halides andtriflates can be treated wtih hexamethyldistannane as described in W. C.Black, et al. J. Med. Chem. 1999, 42, 1274, to give Me₃SnR₆.

EXAMPLES Example 16-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-2-(4H-thieno[3,2-b]pyrrol-5-yl)-quinolineExample 1A (2R)-2-Methylpyrrolidine

A flask containing 20 mL (20 mmol) of a 1M solution of LiAlH₄ in THF wascooled to 0° C. To this well stirred solution was added 1.35 g (5.0mmol) of [(2S)-5-oxopyrrolidin-2-yl]methyl 4-methylbenzenesulfonate (CAS#51693-17-5) in 50 mL of THF. The reaction was allowed to warm to 23°C., and stirred for 60 hours, then quenched by slow addition of 3 gramsof powdered sodium sulfate decahydrate. After one hour, the solids wereremoved by filtration, and washed with isopropyl ether. Some loss ofsolvent to evaporation occurred, so the filtrate and washings werecombined and diluted with isopropanol to 50 mL total volume. 40 mL ofthe solution was treated with 600 mg (4.0 mmol) of L-tartaric acid inmethanol. After concentration under vacuum, a syrup was obtained whichsolidified on standing, to give a quantitative yield (960 mg) of(2R)-methylpyrrolidine L-tartrate as a white powder.

Example 1B (2R)-2-Methyl-1-[2-(4-nitrophenyl)ethyl]pyrrolidine

Example 1A (4.0 g, 17.0 mmol), 1-(2-bromoethyl)-4-nitrobenzene (9.8 g,43 mmol), and potassium carbonate (12 g, 85 mmol), were combined in DMF(20 mL) in a sealed tube at 50° C. and stirred vigorously for 16 hours.The mixture was allowed to cool to room temperature, diluted withdiethyl ether (100 mL), washed with water (2 times, 100 mL and then 50mL), and extracted with 1M HCl (2 times, 50 mL and 25 mL). The aqueousacidic extractions were combined, washed with diethyl ether (50 mL),cooled to 0° C., adjusted to pH 14 with 50% NaOH solution, and extractedwith dichloromethane (3 times, 50 mL). The dichloromethane extractionswere combined, dried (MgSO₄), filtered, and the filtrate concentrated toprovide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 1.08 (d, J=6 Hz, 3H), 1.43 (m, 1 H), 1.75 (m, 2 H), 1.93 (m, 1 H), 2.19 (q, J=9 Hz, 1 H),2.34 (m, 2 H), 2.91 (m, 2 H), 3.03 (m, 1 H), 3.22 (td, J=8, 3 Hz, 1 H),7.38 (d, J=9 Hz, 2 H), 8.15 (d, J=9 Hz, 2 H); MS (DCl/NH₃) m/z 235(M+H)⁺.

Example 1C 4-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}aniline

The product from Example 1B (3.85 g, 16.4 mmol) was hydrogenated using10% Pd/C (0.39 g) in methanol (20 mL) under 1 atm H₂ for 16 hours. Afterthe H₂ was replaced with N₂, the mixture was diluted with methanol (150mL), stirred for 15 minutes, filtered, and the filtrate was concentratedto provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 1.11 (d, J=6Hz, 3 H), 1.43 (m, 1 H), 1.74 (m, 2 H), 1.90 (m, 1 H), 2.25 (m, 3 H),2.70 (m, 2 H), 2.97 (m, 1 H), 3.24 (td, J=9, 3 Hz, 1 H), 3.55 (s, 2 H),6.63 (d, J=8 Hz, 2 H), 7.01 (d, J=8 Hz, 2 H); MS (DCl/NH₃) m/z 205(M+H)⁺.

Example 1D2,2-Dimethyl-N-(4-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}phenyl)propanamide

The product from Example 1C (2.77 g, 14 mmol) was dissolved in anhydrousdichloromethane (70 mL) under nitrogen, treated with triethylamine (2.3mL, 16 mmol), cooled to 0° C., treated with trimethylacetyl chloride(1.9 mL, 15 mmol), stirred at ambient temperature for 60 hours andtreated with 1M NaOH (40 mL). The layers were separated and the aqueouslayer was extracted with dichloromethane (2 times, 40 mL). The combineddichloromethane layers were dried (MgSO₄), filtered, and the filtratewas concentrated to provide 4.0 g of the title compound. ¹H NMR (300MHz, CDCl₃) δ 1.10 (d, J=6 Hz, 3 H), 1.31 (s, 9 H), 1.44 (m, 1 H), 1.76(m, 2 H), 1.92 (m, 1 H), 2.18 (q, J=9 Hz, 1 H), 2.27 (m, 2 H), 2.78 (m,2 H), 2.99 (m, 1 H), 3.23 (td, J=9, 3 Hz, 1 H), 7.17 (d, J=8 Hz, 2 H),7.44 (d, J=8 Hz, 2 H); MS (DCl/NH₃) m/z 289 (M+H)⁺.

Example 1EN-(2-Formyl-4-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}phenyl)-2,2-dimethylpropanamide

The product from Example 1D (4.0 g, 13.9 mmol) under nitrogen inanhydrous diethyl ether (140 mL) was treated withN,N,N′N′-tetramethylethylenediamine (6.5 mL, 43 mmol), cooled to −5° C.,treated with n-butyllithium (16.7 mL of a 2.5 M solution in hexanes)over 10 minutes, stirred for 4 hours at ambient temperature, cooled to−5° C., treated all at once with anhydrous N,N-dimethylformamide (6.5mL, 83 mmol), stirred for 16 hours at ambient temperature, diluted withdiethyl ether (100 mL), washed with water (75 mL), washed with brine,dried (MgSO₄), filtered, and the filtrate was concentrated. The residuewas purified by chromatography on silica gel eluting with a gradient of2%, 3.5%, 5%, and 7.5% (9:1 MeOH:conc NH₄OH) in dichloromethane toprovide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 1.10 (d, J=6 Hz, 3H), 1.35 (s, 9 H), 1.44 (m, 1 H), 1.75 (m, 2 H), 1.93 (m, 1 H), 2.19 (q,J=9 Hz, 1 H), 2.31 (m, 2 H), 2.85 (m, 2 H), 3.01 (m, 1 H), 3.23 (td,J=8, 3 Hz, 1 H), 7.47 (dd, J=8, 2 Hz, 1 H), 7.51 (d, J=2 Hz, 1 H), 8.71(d, J=8 Hz, 1 H), 9.92 (s, 1 H), 11.31 (s, 1 H); MS (DCl/NH₃) m/z 317(M+H)⁺.

Example 1F 2-Amino-5-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}benzaldehyde

The product from Example 1E (2.46 g, 7.8 mmol) in 3M HCl (40 mL) washeated at 80° C. for 4 hours, allowed to cool to room temperature, andcarefully poured into a mixture of 1M NaOH (250 mL) and dichloromethane(75 mL). The layers were separated and the aqueous layer was extractedwith dichloromethane (2 times, 75 mL). The combined dichloromethanelayers were dried (MgSO₄), filtered, and the filtrate was concentrated.The residue was purified by chromatography on silica gel eluting with agradient of 2%, 3.5% and 5% (9:1 MeOH:conc NH₄OH) in dichloromethane toprovide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 1.12 (d, J=6 Hz, 3H), 1.50 (m, 1 H), 1.76 (m, 2 H), 1.93 (m, 1 H), 2.25 (m, 3 H), 2.76 (m,2 H), 2.99 (m, 1 H), 3.25 (td, J=9, 3 Hz, 1 H), 5.99 (s, 2 H), 6.60 (d,J=8 Hz, 1 H), 7.19 (dd, J=8, 2 Hz, 1 H), 7.31 (d, J=2 Hz, 1 H), 9.85 (s,1 H); MS (DCl/NH₃) m/z 233 (M+H)⁺.

Example 1G6-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-2-(4H-thieno[3,2-b]pyrrol-5-yl)-quinoline

The product from Example 1F (23 mg, 0.1 mmol) and1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone (Maybridge Chemical CompanyLtd., catalog number SEW 02099) (10 mg, −0.06 mmol) were combined inethanol 0.2 mL and treated with one drop of a saturated solution ofpotassium hydroxide in ethanol and heated at 80° C. for 16 hours. Themixture was allowed to cool to room temperature and concentrated. Theresidue was purified by chromatography on silica gel eluting with agradient of 2% and 3.5% of (9:1 MeOH:conc NH₄OH) in dichloromethane toprovide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 1.13 (d, J=6.10Hz, 3 H), 1.46 (m, 1 H), 1.77 (m, 2 H), 1.94 (m, 1 H), 2.24 (q, J=8.82Hz, 1 H), 2.37 (m, 2 H), 2.98 (m, 2 H), 3.12 (m, 1 H), 3.29 (td, J=8.48,2.71 Hz, 1 H), 6.98 (dd, J=5.76, 0.68 Hz, 1 H), 7.06 (s, 1 H), 7.18 (d,J=5.43 Hz, 1 H), 7.56 (m, 2 H), 7.72 (d, J=8.82 Hz, 1 H), 7.92 (d,J=8.14 Hz, 1 H), 8.03 (d, J=8.82 Hz, 1 H), 9.89 (br. s, 1 H); MS(DCl/NH₃) [M+H]⁺ at 362.

Example 23-Methyl-2-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-benzo[4,5]imidazo[2,1-b]thiazole

The title compound was prepared using the procedure described in Example1G substituting1-(3-methyl-benzo[4,5]imidazo[2,1-b]thiazol-2-yl)-ethanone (Key OrganicsLimited/Bionet Research, catalog number 1r-1190) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.14(d, J=6.10 Hz, 3 H), 1.47 (m, 1 H), 1.78 (m, 2 H), 1.95 (m, 1 H), 2.25(q, J=8.59 Hz, 1 H), 2.39 (m, 2 H), 3.02 (m, 2 H), 3.13 (m, 1 H), 3.20(s, 3 H), 3.29 (td, J=8.48, 2.71 Hz, 1 H), 7.28 (m, 1 H), 7.40 (td,J=7.71, 1.19 Hz, 1 H), 7.66 (m, 3 H), 7.82 (d, J=7.80 Hz, 1H), 7.90 (d,J=8.14 Hz, 1 H), 8.05 (d, J=9.16 Hz, 1 H), 8.18 (d, J=8.48 Hz, 1 H); MS(DCl/NH₃) [M+H]⁺ at 427.

Example 32-(2-Methyl-imidazo[1,2-a]pyridin-3-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example1G substituting 1-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-ethanone (KeyOrganics Limited/Bionet Research, catalog number 1j-043) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.16(d, J=6.10 Hz, 3 H), 1.49 (m, 1 H), 1.79 (m, 2 H), 1.96 (m, 1 H), 2.27(m, 1 H), 2.43 (m, 2 H), 2.78 (s, 3 H), 3.05 (m, 2 H), 3.15 (m, 1 H),3.32 (m, 1 H), 6.90 (td, J=6.95, 1.36 Hz, 1 H), 7.29 (m, 1 H), 7.63 (m,3 H), 7.71 (d, J=8.48 Hz, 1 H), 8.05 (d, J=8.48 Hz, 1 H), 8.19 (d,J=8.82 Hz, 1 H), 9.69 (dt, J=7.04, 1.06 Hz, 1 H); MS (DCl/NH₃) [M+H]⁺ at371.

Example 42-(4H-Benzo[1,3]dioxin-6-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example1G substituting 1-(4H-benzo[1,3]dioxin-6-yl)-ethanone (Goswami, J., et.al. J. Indian Chem. Soc., 2002, 79(5), 469–471) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.14(d, J=6.10 Hz, 3 H), 1.47 (m, 1 H), 1.78 (m, 2 H), 1.95 (m, 1 H), 2.25(m, 1 H), 2.40 (m, 2 H), 3.03 (m, 2 H), 3.13 (m, 1 H), 3.30 (m, 1 H),5.03 (s, 2 H), 5.31 (s, 2 H), 7.01 (d, J=8.48 Hz, 1 H), 7.60 (dd,J=8.48, 2.03 Hz, 1 H), 7.62 (s, 1 H), 7.78 (d, J=8.48 Hz, 1 H), 7.88 (d,J=2.03 Hz, 1 H), 7.92 (dd, J=8.65, 2.20 Hz, 1 H), 8.04 (d, J=8.48 Hz, 1H), 8.13 (d, J=8.48 Hz, 1 H); MS (DCl/NH₃) [M+H]⁺ at 375.

Example 56-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-2-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl-quinoline

The title compound was prepared using the procedure described in Example1G substituting 1-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl-ethanone for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.15(d, J=6.10 Hz, 3 H), 1.49 (m, 1 H), 1.79 (m, 2 H), 1.96 (m, 1 H), 2.27(m, 1 H), 2.43 (m, 2 H), 3.05 (m, 2 H), 3.15 (m, 1 H), 3.32 (m, 1 H),7.68 (dd, J=8.48, 2.03 Hz, 1 H), 7.73 (d, J=1.70 Hz, 1 H), 8.13 (d,J=8.48 Hz, 1 H), 8.30 (d, J=8.48 Hz, 1 H), 8.56 (s, 1 H), 8.65 (d,J=7.12 Hz, 1 H), 8.79 (d, J=8.48 Hz, 1 H), 8.94 (d, J=7.12 Hz, 1 H); MS(DCl/NH₃) [M+H]⁺ at 359.

Example 62-Benzothiazol-2-yl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example1G substituting 1-benzothiazol-2-yl-ethanone (Oakwood Products, Inc.,catalog number 9660) for 1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. ¹HNMR (300 MHz, CDCl₃) δ 1.15 (d, J=6.10 Hz, 3 H), 1.48 (m, 1 H), 1.77 (m,2 H), 1.96 (m, 1 H), 2.27 (q, J=8.48 Hz, 1 H), 2.42 (m, 2 H), 3.06 (m, 2H), 3.15 (m, 1 H), 3.31 (m, 1 H), 7.44 (td, J=7.63, 1.36 Hz, 1 H), 7.52(td, J=7.63, 1.36 Hz, 1 H), 7.66 (dd, J=8.48, 2.03 Hz, 1 H), 7.69 (s, 1H), 7.99 (d, J=7.12 Hz, 1 H), 8.13 (m, 2 H), 8.24 (d, J=8.48 Hz, 1 H),8.47 (d, J=8.82 Hz, 1 H); MS (DCl-NH₃) [M+H]⁺ at 374.

Example 73-Benzotriazol-1-ylmethyl-2-methyl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example1G substituting 4-benzotriazol-1-yl-butan-2-one (Katritzky, A. R., et.al. J. Org. Chem., 2001, 66(16), 5606–5612) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.11(d, J=5.76 Hz, 3 H), 1.45 (m, 1 H), 1.76 (m, 2 H), 1.93 (m, 1 H), 2.21(m, 1 H), 2.35 (m, 2 H), 2.77 (s, 3 H), 2.96 (m, 2 H), 3.07 (m, 1 H),3.26 (m, 1 H), 6.01 (s, 2 H), 7.32–7.47 (m, 4 H), 7.57 (m, 2 H), 7.94(d, J=8.48 Hz, 1 H), 8.13 (m, 1 H); MS (DCl/NH₃) [M+H]⁺ at 386.

Example 82-[1,3]Dioxolo[4,5-b]pyridin-6-yl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example1G substituting 1-[1,3]dioxolo[4,5-b]pyridin-6-yl-ethanone (Dallacker etal., Z. Naturforsch. B Anorg. Chem. Org. Chem., 1979, 34, 1729–1733) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.15(d, J=6.10 Hz, 3 H), 1.49 (m, 1 H), 1.79 (m, 2 H), 1.96 (m, 1 H), 2.27(m, 1 H), 2.43 (m, 2 H), 3.05 (m, 2 H), 3.15 (m, 1 H), 3.32 (m, 1 H),6.15 (s, 2 H), 7.62 (dd, J=8.48, 1.70 Hz, 1 H), 7.64 (s, 1 H), 7.78 (d,J=8.48 Hz, 1 H), 7.97 (d, J=1.70 Hz, 1 H), 8.04 (d, J=8.48 Hz, 1 H),8.15 (d, J=8.48 Hz, 1 H), 8.37 (d, J=2.03 Hz, 1 H); MS (DCl/NH₃) [M+H]⁺at 362.

Example 96-{2-[(2R)-2-Methyl-pyrrolidin-1-yl]-ethyl}-2-(6-methyl-thiazolo[3,2-b][1,2,4]triazol-5-yl)-quinoline

The title compound was prepared using the procedure described in Example1G substituting 1-(6-methyl-thiazolo[3,2-b][1,2,4]triazol-5-yl)-ethanone(Key Organics Limited/Bionet Research, catalog number 7M-582S) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.17(d, J=6 Hz, 3 H), 1.48 (m, 1 H), 1.82 (m, 2 H), 2.02 (m, 1 H), 2.33 (q,J=9 Hz, 1 H), 2.46 (m, 2 H), 2.96 (s, 3 H), 3.05 (m, 2 H), 3.18 (m, 2H), 7.70 (d, J=9 Hz, 1 H), 7.78 (s, 1 H), 7.90 (d, J=9 Hz, 1 H), 7.99(d, J=9 Hz, 1 H), 8.25 (s, 1 H), 8.35 (d, J=9 Hz, 1 H); MS (DCl/NH₃) m/z378 (M+H)⁺.

Example 102-(2,3-Dihydro-imidazo[2,1-b]thiazol-6-yl)-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline

The title compound was prepared using the procedure described in Example1G substituting 1-(2,3-dihydro-imidazo[2,1-b]thiazol-6-yl)-ethanone(Kaugars, G.; et. al. Heterocycles 1994, 38, pages 2593–2604) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.17(d, J=6 Hz, 3 H), 1.47 (m, 1 H), 1.81 (m, 2 H), 2.00 (m, 1 H), 2.34 (q,J=9 Hz, 1 H), 2.47 (m, 2 H), 3.03 (m, 2 H), 3.17 (m, 1 H), 3.28 (m, 1H), 3.97 (t, J=9 Hz, 2 H), 4.35 (t, J=9 Hz, 2 H), 7.63 (dd, J=9 Hz, J=3Hz, 1 H), 7.72 (d, J=3 Hz, 1 H), 7.93 (d, J=9 Hz, 2 H), 7.94 (s, 1 H),8.23 (d, J=9 Hz, 1 H); MS (DCl/NH₃) m/z 365 (M+H)⁺.

Example 112-(2,7-Dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl)-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinolineExample 11A 1-(2,7-Dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl)-ethanone

A solution of 3-dimethylaminomethylene-pentane-2,4-dione (4 g, 25.8mmol) and 3-amino-5-methylpyrazole (2.45 g, 24.5 mmol) in ethanol (50mL) was heated to reflux for 2 hrs, then cooled to ambient temperatureand stirred over night. The solid precipitate was collected byfiltration and washed with cold ethanol (50 mL). The solid was driedunder vacuum to provided 3.8 g of the title compound. ¹H NMR (300 MHz,CD₃OD) δ 2.52 (s, 3 H), 2.68 (s, 3 H), 3.07 (s, 3 H), 6.55 (s, 1 H),6.87 (s, 1 H); MS (DCl/NH₃) m/z 190 (M+H)⁺.

Example 11B2-(2,7-Dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl)-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline

The title compound was prepared using the procedure described in Example1G substituting the product from Example 11A for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.17(d, J=6 Hz, 3 H), 1.48 (m, 1 H), 1.82 (m, 2 H), 2.03 (m, 1 H), 2.35 (q,J=9 Hz, 1 H), 2.47 (m, 2 H), 2.56 (s, 3 H), 2.91 (s, 3 H), 3.06 (m, 2H), 3.20 (m, 1 H), 3.28 (m, 1 H), 6.59 (s, 1 H), 7.76 (dd, J=9 Hz, J=3Hz, 1 H), 7.78 (d, J=9 Hz, 1 H), 7.88 (d, J=3 Hz, 1 H), 8.05 (d, J=9 Hz,1 H), 8.45 (d, J=9 Hz, 1 H), 8.66 (s, 1 H); MS (DCl/NH₃) m/z 386 (M+H)⁺.

Example 122-Methyl-3-{6-[2-([2R]-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-[1,8]naphthyridine

The title compound was prepared using the procedure described in Example1G substituting 1-(2-methyl-[1,8]naphthyridin-3-yl)-ethanone (Reddy, K.V.; et. al. J. Indian Chem. Soc. 1986, 63, pages 443–445) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.16(d, J=6 Hz, 3 H), 1.48 (m, 1 H), 1.76 (m, 1 H), 1.84 (m, 1 H), 1.97 (m,2 H), 2.28 (q, J=9 Hz, 1 H), 2.43 (m, 2 H), 2.95 (s, 3 H), 3.08 (m, 2H), 3.17 (m, 1 H), 6.59 (s, 1 H), 7.47 (dd, J=6 Hz, J=3 Hz, 1 H), 7.62(d, J=6 Hz, 1 H), 7.69 (dd, J=6 Hz, J=1.5 Hz, 1 H), 7.73 (s, 1 H), 8.11(d, J=6 Hz, 1 H), 8.23 (dd, J=6 Hz, J=1.5 Hz, 1 H), 8.25 (d, J=6 Hz, 1H), 8.30 (s, 1 H); MS (DCl/NH₃) m/z 383 (M+H)⁺.

Example 136-{6-[2-([2R]-2-Methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-quinoxalineExample 13A 1-Quinoxalin-6-yl-ethanone

A solution of 6-bromo-quinoxaline (261 mg, 1.25 mmol),1-ethoxyvinyltri-n-butyltin (0.47 mL, 1.4 mmol), palladium(II) acetate(16 mg) and tri-t-butylphosphonium tetrafluoroborate (41 mg) inanhydrous DMF (4 mL) under a nitrogen atmosphere was heated at 120° C.for 1 hr. The reaction mixture was cooled to ambient temperature andpartitioned between ethyl acetate (25 mL) and H₂O (10 mL). The organicextraction was washed with brine, dried (MgSO₄), filtered, andconcentrated. The concentrate was chromatographed on silica gel elutingwith ethyl acetate:hexanes (1:1) to provide 110 mg of the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ 2.79 (s, 3 H), 8.18 (d, J=9 Hz, 1H), 8.36 (dd, J=9 Hz, J=3 Hz, 1 H), 8.70 (d, J=3 Hz, 1 H), 8.95 (s, 2H); MS (DCl/NH₃) m/z 173 (M+H)⁺.

Example 13B6-{6-[2-([2R]-2-Methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-quinoxaline

The title compound was prepared using the procedure described in Example1G substituting the product of Example 13A for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.18(d, J=6 Hz, 3 H), 1.47 (m, 1 H), 1.83 (m, 2 H), 2.04 (m, 1 H), 2.37 (q,J=9 Hz, 1 H), 2.51 (m, 2 H), 3.07 (m, 2 H), 3.21 (m, 2 H), 7.74 (dd, J=9Hz, J=3 Hz, 1 H), 7.83 (d, J=3 Hz, 1 H), 8.13 (d, J=9 Hz, 1 H), 8.22 (d,J=9 Hz, 1 H), 8.25 (d, J=9 Hz, 1 H), 8.44 (d, J=9 Hz, 1 H), 8.75 (dd,J=9 Hz, J=3 Hz, 1 H), 8.84 (d, J=3 Hz, 1 H), 8.94 (dd, J=9 Hz, J=3 Hz, 2H); MS (DCl/NH₃) m/z 369 (M+H)⁺.

Example 146-(2-Methyl-benzothiazol-5-yl)-2-[2-(2R-methyl-pyrrolidin-1-yl)-ethyl]-quinolineExample 14A 6-Bromo-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline

(2R)-2-Methylpyrrolidine L-tartrate (7.00 g, 0.0298 mole, milled),potassium carbonate (9.04 g, 0.0655 mole, milled), and acetonitrile (190mL) were combined and heated at 60° C. with agitation for 48 hours. Themixture was allowed to cool to 30° C., and treated with the product fromExample 42C (8.00 g, 0.0197 mole). The reaction mixture was heated at˜60° C. for 36 hours and then distilled down to ˜¼ volume, and isopropylacetate (200 mL) was added. The mixture was washed with 5% NaHCO₃ aq.solution (200 mL×2), and 25% brine (200 mL). The upper organic was driedover anhydrous sodium sulphate, filtered, and the filtrate wasconcentrated to dryness. The crude product was purified with ashort-path silica gel column eluted with heptane:ethyl acetate:TEA(60:40:1) to give 5.8 g (92% yield) of product as an oil, whichsolidified on standing; mp 49–50° C. (uncorrected); MS (ESI): 319, 311(M+H)⁺; ¹H-NMR (CDCl₃) δ 7.95 (1 H, d, J=8.5 Hz), 7.91 (1H, d, J=2.2Hz), 7.89 (1H, d, J=8.9 Hz), 7.72 (1H, dd, J=8.9, 2.2 Hz), 7.35 (1H, d,J=8.5 Hz), 3.23 (2H, m), 3.18 (2H, m), 2.55 (1H, m), 2.38 (1H, m), 2.25(1H, q, J=8.9 Hz), 1.93 (1H, m), 1.80 (1H, m), 1.71 (1H, m), 1.42 (1H,m), 1.11 (3H, d, J=6.0 Hz); ¹³C-NMR (CDCl₃) δ 161.3, 146.1, 134.7,132.3, 130.3, 129.2, 127.6, 122.2, 119.2, 59.9, 54.0, 53.6, 38.6, 33.0,22.0, 19.4.

Example 14B6-(2-Methyl-benzothiazol-5-yl)-2-[2-(2R-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

Tetrakis(triphenylphosphine) palladium (0) (28.8 mg, 0.025 mmol),2-(dicyclohexylphosphino)biphenyl (17.5 mg, 0.05 mmol),2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazole(0.375 mmol), and sodium carbonate (40.0 mg, 0.375 mmol) were combinedin 1,2-dimethoxyethane (4 mL) and water (1.5 mL). The mixture was thentreated with the product from Example 14A (80 mg, 0.25 mmol) and heatedat 80° C. for 24 hours. The reaction mixture was allowed to cool to roomtemperature and diluted with ethyl acetate (20 mL). The organic layerwas separated, washed with 5% NaHCO₃ (25 mL×3), 25% brine (25 mL), driedover Na₂SO₄, filtered, and the filtrate was concentrated to dryness. Theresidue was purified by column chromatography(heptane:acetone:CH₂Cl₂:TEA (60:40:5:1) to provide the title compound.The title compound was treated with HCl in IPA:ethyl acetate to give thetrihydrochloride salt. Mp=182–183° C.; MS (ESI) 388 (M+H)⁺; ¹H NMR(trihydrochloride, DMSO-d₆, 400 MHz) d 8.92 (1H, d), 8.63 (1H, d), 8.44(2H, m), 8.40 (1H, d), 8.21 (1H, d), 8.00 (1H, d), 7.90 (1H, dd), 3.94(1H, br, m), 3.75 (2H, br, m), 3.52 (3H, br, m), 3.26 (1H, br, m), 2.93(3H, s), 2.21 (1H, m), 2.00 (2H, br, m), 1.70 (1H, br, m), 1.43 (3H, br,d).

Example 157-(2-Methyl-benzothiazol-5-yl)-3-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-isoquinolineExample 15A Methyl 5-bromo-2-iodobenzoate

To a stirred slurry of methyl 2-iodo-benzoate (5.0 g, 0.019 mol) andN-bromosuccinimide (3.74 g, 0.021 mol) in acetic acid (10 mL) was addedconcentrated H₂SO₄ (10 mL) dropwise, keeping the temperature at 20–40°C. The mixture was stirred at room temperature for 88 hours and thenheated at 50° C. for 4 hours. The mixture was cooled to 10° C., treatedwith 40 g of ice water, and extracted with 50 mL of CH₂Cl₂. The organicphase was washed in succession with 2×50 mL 5% NaHCO₃, 50 mL 10%Na₂S₂O₃, 50 mL water, and concentrated to colorless oil. The residue waspurified by column chromatography (silica gel, 10:90 EtOAc:hexane) toprovide the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 7.92 (d, J=4 Hz,1H), 7.83 (d, J=8 Hz, 1H), 7.27 (dd, J=8, 4 Hz, 1H), 3.92 (s, 3H); MS(DCl/NH₃) [M+NH₄]⁺ at 358, [M+NH₃NH₄]⁺ at 375.

Example 15B (5-Bromo-2-iodophenyl)methanol

To a stirred mixture of NaBH₄ (11.18 g, 0.296 mol) in EtOH (200 mL) at5° C. was added the product from Example 15A (50.4 g, 0.148 mol) in THF(100 mL). The mixture was alowed to warm to room temperature and stirredfor 18 hours. The mixture was treated with additional NaBH₄ (8.4 g,0.222 mol) and was stirred for 22 hours. The mixture was cooled to 0°C., treated with 100 mL of 15% aqueous citric acid slowly, and extractedwith 600 mL of CH₂Cl₂. The organic phase was washed with 200 mL of 15%NaCl and concentrated to provide the title compound. ¹H NMR (CDCl₃, 400MHz) δ 7.64 (d, J=8 Hz, 1H), 7.61 (d, J=4 Hz, 1H), 7.12 (dd, J=4, 8 Hz,1H), 4.63 (d, J=8 Hz, 2H), 1.98 (t, J=8 Hz, 1H). MS (DCl/NH₃) [M+NH₄]⁺at 330, [M+NH₄−H₂O]⁺ at 312.

Example 15C 5-Bromo-2-iodobenzaldehyde

A solution of oxalyl chloride (1.53 g, 0.012 mol) in CH₂Cl₂ (15 mL) wascooled to −70° C., and DMSO (1.41 g, 0.018 mol) in CH₂Cl₂ (15 mL) wasadded at −65 to −70° C. The mixture was stirred under nitrogen for 10minutes at −70° C. and then treated with the product from Example 15B(2.35 g, 7.5 mmol) in 60 mL CH₂Cl₂. The slurry was stirred at −65° C.for 15 minutes and treated with triethylamine (3.8 g, 0.037 mol). Themixture was allowed to warm to −10° C. over 1 hour. The mixture wastreated with 20 mL of water and allowed to warm to room temperature. Theorganic layer was separated and concentrated to provide the titlecompound. ¹H NMR (CDCl₃, 400 MHz) δ 9.97(s, 1H), 7.97 (d, J=4 Hz, 1H),7.79 (d, J=8 Hz, 1H), 7.40 (dd, J=4, 8 Hz, 1H). MS (DCl/NH₃) [M+NH₄]⁺ at328.

Example 15D N-[(1E)-(5-Bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine

The product from Example 15C (2.28 g, 7.3 mmol) in THF (10 mL) wastreated with t-butylamine (1.61 g, 22.0 mmol) and stirred under nitrogenat room temperature for 40 hours. The mixture was concentrated underreduced pressure and the residue was dissolved in 30 mL of methylenechloride. The methylene chloride was washed with 10 mL water andconcentrated to provide the title compound which was used in the nextstep without further purification. ¹H NMR (CDCl₃, 400 MHz) δ 8.29 (s,1H), 8.05 (d, J=4 Hz, 1H), 7.66 (d, J=8 Hz, 1H), 7.19 (dd, J=4, 8 Hz,1H), 1.34 (s, 9H). MS (DCl/NH₃) 366 [M+H]⁺.

Example 15E 2-(7-Bromo-3-isoquinolinyl)ethanol

The product from Example 15D (1.3 g, 3.6 mmol), 3-butyn-1-ol (0.3 g, 4.3mmol), CuI (0.04 g, 0.2 mmol), and PdCl₂(PPh₃)₂ (0.08 g, 0.1 mmol) werecombined in toluene (15 mL). The mixture was treated withdiisopropylamine (0.54 g, 5.3 mmol) and stirred at room temperature for4 hours. The mixture was then treated with additional CuI (0.07 g, 0.4mmol) and heated at 100° C. for 4 hours. The mixture was allowed to coolto room temperature, diluted with 30 mL CH₂Cl₂, and filtered. Thefiltrate was washed with 2×10 mL 15% NaCl and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel,10:90 MeOH:CHCl₃) to provide the title compound. ¹H NMR (CDCl₃, 400 MHz)δ 9.08 (s, 1H), 8.09 (d, J=4 Hz, 1H), 7.73 (dd, J=8, 4 Hz, 1H), 7.63 (d,J=8 Hz, 1H), 7.48 (s, 1H), 4.08 (t, J=4 Hz, 2H), 3.92 (s, 1H), 3.15 (t,J=4 Hz, 2H). ¹³C NMR (CDCl₃, 100 MHz) δ 153.8, 150.3, 134.5, 133.8,129.4, 127.6, 120.0, 118.6, 62.3, 39.4. MS (DCl/NH₃) 252, 254 [M+H]⁺.

Example 15F7-Bromo-3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}isoquinoline

The product from Example 15E (0.5 g, 2.0 mmol) and triethylamine (0.5 g,4.9 mmol) were combined in THF (15 mL) at −15° C. The mixture wastreated with methanesulfonyl chloride (0.24 g, 2.1 mmol) and stirred at0–10° C. for 2 hours. The mixture was treated with additionalmethanesulfonyl chloride (0.2 mmol) and stirred at room temperature for16 hours. The mixture was treated with (2R)-2-methylpyrrolidinehydrochloride (0.72 g, 6.0 mmol) and K₂CO₃ (0.27 g, 2.0 mmol) inacetonitrile (25 mL) and then the mixture was heated at 60° C. for 20hours. The mixture was allowed to cool to room temperature and wasconcentrated under reduced pressure. The residue was dissolved in 20 mLCH₂Cl₂, washed with 5 mL of water and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel,10:90 MeOH:CHCl₃) to provide the title compound. ¹H NMR (CDCl₃, 400 MHz)δ 9.10 (s, 1H), 8.09 (d, J=4 Hz, 1H), 7.72 (dd, J=12, 4 Hz, 1H), 7.64(d, J=12 Hz, 1H), 7.58 (s, 1H), 3.46–3.40 (m, 2H), 3.34–3.29 (m, 2H),2.91–1.85 (m, 1H), 2.81–2.68 (m, 1H), 2.59–2.49 (m, 1H), 2.11–2.02 (m,1H), 2.00–1.91 (m, 1H), 1.88–1.79 (m, 1H), 1.71–1.61 (m, 1H), 1.32 (d,J=8 Hz, 3H). ¹³C NMR (CDCl₃, 100 MHz) δ 152.5, 150.6, 134.5, 133.6,129.2, 127.8, 127.7, 120.0, 118.7, 61.7, 53.7, 53.4, 36.0, 32.4, 21.9,17.9. MS (DCl/NH₃) 319, 321 [M+H]⁺.

Example 15G7-(2-Methyl-benzothiazol-5-yl)-3-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-isoquinoline

The product from Example 15F (0.30 g, 0.9 mmol),2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazole(0.39 g, 1.4 mmol), 2-(dicyclohexylphosphino)biphenyl (66 mg, 0.2 mmol),and PdCl₂(PPh₃)₂ (66 mg, 0.1 mmol) were combined in isopropanol (15 mL).The mixture was treated with a solution of Na₂CO₃ (0.15 g, 1.4 mmol, in5 mL water) and heated at 65° C. for 7 hours. After cooling to roomtemperature, the mixture was diluted with 20 mL of CH₂Cl₂ and filtered.The filtrate was concentrated under reduced pressure, the residue wasre-dissolved in 20 mL of CH₂Cl₂ and washed with 5 ml of water. Themethylene chloride layer was extracted with 10 ml of 2N HCl. The aqueousHCl layer was treated with 20 mL of CH₂Cl₂ and basified with 4N NaOH.The methylene chloride layer was concentrated to oily residue which waspurified by column chromatography (silica gel, 10:90:1 MeOH:CHCl₃:Et₃N)to provide the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 9.24 (s, 1H),8.24 (dd, 1H), 8.15 (dd, 1H), 7.97 (dd, J=3, 12 Hz, 1H), 7.90 (d, J=8Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.67 (dd, J=3, 12 Hz, 1H), 7.61 (s, 1H),3.46–3.39 (m, 1H), 3.35–3.28 (m, 1H), 2.86 (s, 3H), 2.88–2.81 (m, 1H),2.73–2.68 (m, 1H), 2.53–2.47 (m, 1H), 2.08–1.58 (4H), 1.30 (d, J=8 Hz,3H). ¹³C NMR (CDCl₃, 400 MHz) δ 167.4, 153.7, 152.3, 151.9, 138.7,138.0, 135.2, 134.8, 129.8, 127.2, 126.6, 125.0, 123.8, 121.5, 120.5,118.4, 61.3, 53.7, 53.7, 36.3, 32.4, 21.8, 20.5, 18.1. MS (DCl/NH₃)[M+H]⁺ at 388.

Example 16 Determination of Biological Activity

To determine the effectiveness of representative compounds of thisinvention as histamine-3 receptor ligands (H₃ receptor ligands), thefollowing tests were conducted according to methods previously described(European Journal of Pharmacology, 188:219–227 (1990); Journal ofPharmacology and Experimental Therapeutics, 275:598–604 (1995); Journalof Pharmacology and Experimental Therapeutics, 276:1009–1015 (1996); andBiochemical Pharmacology, 22:3099–3108 (1973)).

Briefly, male Sprague-Dawley rat brain cortices were homogenized (1 gtissue/10 mL buffer) in 50 mM Tris-HCl/5 mM EDTA containing proteaseinhibitor cocktail (Calbiochem) using a polytron set at 20,500 rpm.Homogenates were centrifuged for 20 minutes at 40,000×g. The supernatantwas decanted, and pellets were weighed. The pellet was resuspended bypolytron homogenization in 40 mL 50 mM Tris-HCl/5 mM EDTA with proteaseinhibitors and centrifuged for 20 minutes at 40,000×g. The membranepellet was resuspended in 6.25 volumes (per gram wet weight of pellet)of 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and aliquots flashfrozen in liquid N₂ and stored at −70° C. until used in assays. Ratcortical membranes (12 mg wet weight/tube) were incubated with(³H)-N-α-methylhistamine (˜0.6 nM) with or without H₃ receptorantagonists in a total incubation volume of 0.5 mL of 50 mM Tris-HCl/5mM EDTA (pH 7.7). Test compounds were dissolved in DMSO to provide a 20mM solution, serially diluted and then added to the incubation mixturesprior to initiating the incubation assay by addition of the membranes.Thioperamide (3 μM) was used to determine nonspecific binding. Bindingincubations were conducted for 30 minutes at 25° C. and terminated byaddition of 2 mL of ice cold 50 mM Tris-HCl (pH 7.7) and filtrationthrough 0.3% polyethylenimine-soaked Unifilter plates (Packard). Thesefilters were washed 4 additional times with 2 mL of ice-cold 50 mMTris-HCl and dried for 1 hour. Radioactivity was determined using liquidscintillation counting techniques. Results were analyzed by Hilltransformation and K_(i) values were determined using the Cheng-Prusoffequation.

Generally, representative compounds of the invention demonstratedbinding affinities in the above assay from about 810 nM to about 0.02nM. Preferred compounds of the invention bound to histamine-3 receptorswith binding affinities from about 100 nM to about 0.02 nM. Morepreferred compounds of the invention bound to histamine-3 receptors withbinding affinities from about 20 nM to about 0.02 nM.

Compounds of the invention are histamine-3 receptor ligands thatmodulate function of the histamine-3 receptor by altering the activityof the receptor. These compounds may be inverse agonists that inhibitthe basal activity of the receptor or they may be antagonists thatcompletely block the action of receptor-activating agonists. Thesecompounds may also be partial agonists that partially block or partiallyactivate the histamine-3 receptor or they may be agonists that activatethe receptor.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

1. A compound of the formula:

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,wherein: Y′ is CH or CF; X, X′, Z, and Z′ are each; R₁ is L₂R₆; R₂ isselected from the group consisting of hydrogen, alkyl, alkoxy, aryl,cycloalkyl, halogen, cyano, and thioalkoxy; R₃ is selected from thegroup consisting of hydrogen, alkyl, alkoxy, halogen, cyano, andthioalkoxy; R_(3a) is selected from the group consisting of hydrogen,methyl, alkoxy, halogen, and cyano; R_(3b) is selected from the groupconsisting of hydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, andthioalkoxy; R₄ and R₅ are each independently selected from the groupconsisting of alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, and (NR_(A)R_(B))alkyl, wherein R_(A) and R_(B) areeach independently selected from the group consisting of hydrogen,alkyl, acyl, and formyl; or R₄ and R₅ taken together with the nitrogenatom to which each is attached form a non-aromatic ring of the formula:

R₆ is a bicyclic or tricyclic ring, each containing at least twoheteroatoms; R₇, R₈, R₉, and R₁₀ at each occurrence are eachindependently selected from the group consisting of hydrogen,hydroxyalkyl, fluoroalkyl, and alkyl; or one of the pair R₇ and R₈ orthe pair R₉ and R₁₀ is taken together to form a C₃–C₆ ring, wherein 0,1, or 2 heteroatoms selected from O, N, or S replace a carbon atom inthe ring; R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selected fromthe group consisting of hydrogen, hydroxy, hydroxyalkyl, alkyl, andfluoro; Q is selected from the group consisting of a bond, O, S, andNR₁₅; L is —[C(R₁₆)(R₁₇)]_(n)—; L₂ is a bond; R₁₅ is selected from thegroup consisting of hydrogen, alkyl, acyl, alkoxycarbonyl, amido, andformyl; R₁₆ and R₁₇ at each occurrence are independently selected fromthe group consisting of hydrogen, alkyl, alkoxy, and fluoro; R₁₈ and R₁₉at each occurrence are each independently selected from the groupconsisting of hydrogen, hydroxy, alkyl, alkoxy, and fluoro; R_(x) andR_(y) at each occurrence are independently selected from the groupconsisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino,dialkylamino, and fluoro, or one of R_(x) or R_(y) represents a covalentbond when taken together with R_(x) or R_(y) on an adjacent carbon atomsuch that a double bond is represented between the adjacent carbonatoms; m is an integer from 1 to 5; n is an integer from 1 to 6; p is aninteger from 2 to 6; and q is an integer from 1 to
 4. 2. The compound ofclaim 1, wherein R₁ is L₂R₆, L₂ is a bond, and R₆ is an aromatic ornon-aromatic 5- to 6-membered ring fused to an aromatic or non-aromatic5- to 10-membered ring, provided that the fused ring system contains atleast two heteroatoms.
 3. The compound of claim 1, wherein R₁ is L₂R₆,L₂ is a bond, and R₆ is selected from the group consisting of4H-thieno[3,2-b]pyrrolyl; benzo[4,5]imidazo[2,1-b]thiazolyl;2-methyl-imidazo[1,2-a]pyridinyl; 4H-benzo[1,3]dioxinyl;[1,2,4]triazolo[1,5-a]pyrimidinyl; benzothiazolyl; benzotriazolyl;[1,3]dioxolo[4,5-b]pyridinyl; 6-methyl-thiazolo[3,2-b][1,2,4]triazolyl;2,3-dihydro-imidazo[2,1-b]thiazolyl;2,7-dimethyl-pyrazolo[1,5-a]pyrimidinyl; [1,8]naphthyridinyl; andquinoxalinyl.
 4. The compound of claim 1, wherein R₄ and R₅ takentogether with the nitrogen atom to which each is attached form a 4- to8-membered non-aromatic ring represented by formula (a).
 5. The compoundof claim 4, wherein at least one substituent represented by R₇, R₈, R₉,and R₁₀ is selected from the group consisting of alkyl, fluoroalkyl, andhydroxyalkyl or at least one substituent represented by R_(x) or R_(y)is selected from the group consisting of hydrogen, hydroxy, and fluoro.6. The compound of claim 1, wherein R₄ and R₅ taken together with thenitrogen atom to which each is attached to form 2-methylpyrrolidine. 7.The compound of claim 1, selected from the group consisting of:6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-(4H-thieno[3,2-b]pyrrol-5-yl)-quinoline;3-methyl-2-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-benzo[4,5]imidazo[2,1-b]thiazole;2-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;2-(4H-benzo[1,3]dioxin-6-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl-quinoline;2-benzothiazol-2-yl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;2-[1,3]dioxolo[4,5-b]pyridin-6-yl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-2-(6-methyl-thiazolo[3,2-b][1,2,4]triazol-5-yl)-quinoline;2-(2,3-dihydro-imidazo[2,1-b]thiazol-6-yl)-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline;2-(2,7-dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl)-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline;2-methyl-3-{6-[2-([2R]-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-[1,8]naphthyridine;and6-{6-[2-([2R]-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-quinoxaline.8. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 in combination with a pharmaceuticallyacceptable carrier.
 9. A method of treating Alzheimer's disease,attention-deficit hyperactivity disorder, schizophrenia, or cognitivedeficits of schizophrenia comprising administering an effective amountof a compound of claim 1.